Anti-viral compounds.

(54) Title: ANTIVIRAL COMPOUNDS.

(54) Title: ANTI-VIRAL COMPOUNDS.

(57) Summary

Compounds effective to inhibit Hepatitis C virus (HCV) replication are disclosed. This invention also relates to methods of making said compounds, to compositions comprising said compounds, and to methods of using said compounds to treat HCV infection.

(57) Abstract

Compounds effective ¡n 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.

<img file="MX346264B_D0001.tif" />

Institute

Mexican Property

Industrial

PATENT TITLE NO. 346264

<td>Headlines):</td><td>ABBVIE BAHAMAS LTD.</td>

<td>Home:</td><td>Sassoon House Shirley Street &amp; Victoria Avenue, New Providence, Nassau, BAHAMAS</td>

Denomination: ANTMRAL COMPOUNDS.

<td>Classification:</td><td>Int.CI.8: A61K31 / 4164; A61K31 / 4184; A61P31 / 14; C07D403 / 14</td>

<td>Inventor (s):</td><td>DAVID A. DEGOEY; WARREN Μ. ΚΑΤΙ; CHARLES W. HUTCHINS; PAMELA L. DONNER; ALLAN C. KRUEGER; JOHN T. RANDOLPH; SACHIN V. PATEL; MARK A MATüLENKO; RYAN G. KEDDY TAMMIE K JINKERSON; DACHUN LIU JOHN K PRATT; ALL W ROCKWAY; CLÁRENCE J. MARING DOUGLAS H HUTCHINSON; CHARLES A. FLENTGE; ROLF WAGNER, DAVID A. BETÉBENNER; KATHY SARRIS; KEVIN R. WOLLER; WILLIAM A. CARROLL; Yl GAO '. . ;</td>

Number »'MX / a / 2013/008763

REQUEST

International filing date!

February 2012

PRIORITY

I Country: Date: Number:

US February 25, 2011 61 / 446,800

Validity: Twenty years

Vei | date: imie4ito: February 24, 2032 the reference patent was granted based on articles 1 ', 2nd section V, 6th I □ c &amp; oi IIL and 00 of Ln. of Industrial Property.

• For example, in accordance with article 23 of the Industrial Property Law, the present document has a twenty-year period, which can be repealed, -counted from the Bcha de ^ esentation of the mternaconal sdMM and eaianft 9i faga of the tariff for keep the 'rights in force. i ts

Guien signs the present title only based on the provisions of the articles t&gt; sections III and 7^or bis 2 of the Industrial Property Law g&gt; rio Oficial dg. the Federation (PO.F) 06/27/1991. amended on 08/02/1994, 10/25/1996, 12/26/1907, 05/17/1999, 01/25/2 &lt;M 06/05 ^^ articles1 ·. 3^or fraction V declared a), 4th and 12th sections I and III of the Regulations of the Mexican Institute of Industrial Property (DOF 12/14/1999, amended on 07/01/2002, 07/15/2004, 07/28 / 2004 and 7/09/2007); items 1^or, 3^or, 4^or, 5^or fraction V declared a), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 07/29/2004, 08/04 2004 and 09/13/2007); one^or, 3^orand 5th subsection a) of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

<img file="MX346264B_D0002.tif" />

IMPI

INSTITVIWMinCANQ MumnÚM INDUCTMAl.

<img file="MX346264B_D0003.tif" />

ANTIVIRALESE COMPOUNDS *

This application claims the benefit of US Provisional Application Serial No. 61 / 446,800, filed on February 25, 2011, the full content of which is incorporated into this application for reference.

FIELD OF THE INVENTION

The present invention relates to compounds effective to inhibit the replication of the Hepatitis C virus (HCV). The present invention also relates to compositions comprising these compounds and to methods of using these compounds to treat HCV infection.

BACKGROUND OF THE INVENTION

HCV is an RNA virus that belongs to the genus Hepacivirus in the Flaviviridae family. The enveloped HCV virion contains a positive strand RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and codes for a single long polyprotein of approximately 3000 amino acids.

The polyprotein comprises a core protein, proteins of

INSTITUTO MEXICAN ·

Dt THE «OFIÍOAO &lt;2— 'INDUSTRY!

envelope E1 and E2, a membrane-bound p7 protein, and the non-structural proteins N53, NS4A, NS4B, NS5A, and NS5B.

HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can be treated with peg-interferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral clearance from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection.

BRIEF DESCRIPTION OF THE INVENTION

In one aspect, the present invention features the compounds of Examples 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 4.61, 4.62, 12.1, and 12.2, and pharmaceutically acceptable salts thereof. These compounds and salts can inhibit HCV replication and are therefore useful for treating HCV infection.

In another aspect, the present invention also features compositions comprising these compounds or salts. The compositions may also include additional therapeutic agents, such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY ¹

INDUSTRIAL X »7-m ~» S¡ · Inhibitors of the internal ribosome entry site (IRES).

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

Furthermore, the present invention presents methods for using the compounds or salts of the present invention, or compositions comprising them, to treat HCV infection. The methods comprise administering a compound or salt of the present invention, or a pharmaceutical composition comprising said compounds, to a patient in need thereof, thereby reducing the level of HCV virus in blood or tissue in the patient.

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

Also, the present invention presents processes for making the compounds or salts of the invention.

Many aspects and embodiments of the present invention are also described in US Patent Application Publication Nos. 2010/03 17568, 2011/0092415, and 2011/0207699, the full contents of which are incorporated into the present application for reference.

<img file="MX346264B_D0004.tif" />

Other features, objectives, and advantages of the present invention are apparent from the following detailed description. However, it should be understood that the detailed description, while indicating preferred embodiments of the invention, are provided by way of illustration only, not 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 OF THE INVENTION

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

DI L3 IYAL | X L2 BZ

I in which:

X is carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_TO or R_F;

Lj and L₂ each are independently selected from link; or C ^ Ce alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆, each of which independently is optionally substituted each time it occurs with one or more R_L;

IMPI nwwtvfoMeucAN ·

- ;. O&gt; IAPROnEM »Ο ^ ΣΪΚΓ

INDUSTRY!.

L₃ is link or -L_s-KL_s'-, in which K is selected from bond, -O-, -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 (R_b) C (0) -, -N (R_b) C (O) O-, -OC (O) N (R_b) -, -N (Rb) S (O) -, -N (R_b)SW)₂-, -S (O) N (R_b) -, -S (O)₂N (Rb) -, -C (O) N (Rb) C (O) -,

-N (Rb) C (O) N (R_b') -, -N (R_b)SW₂N (Rb ') -, O -N (R_b) S (O) N (R_b’)-;

A and B are each independently carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more R_to;

D is carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_to; or D is carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle and is optionally substituted with one or more R_TO, or J is -SF₅ or D is hydrogen or R_TO;

Y is selected from -T'-C (R₁ R₂) N (R₅) -TR_D, -T'C (R₃R₄) C (R₆R7) -T-Rd, -Lk-T-Rd, or -L_k-AND;

R₁ and R₂ are each independently R_c, and Rs is R_b; or Ri is R_c, and R₂ and Re, 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_TO;

R3, R4, Re, and R7 are each independently Rc '&gt; or R₃ and R_s are each independently R_c, and R₄ and R7, taken together with the atoms to which they are attached,

<img file="MX346264B_D0005.tif" />

IMPI

Ο * ΝΠΗΌ MIXtCANO mi * noFiH&gt; AD INDUSTRIAL form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more R_TO;

Z is selected from -T'-C (R₈R9) N (Ri2) -T-Rd, -T'C (R₁₀Rii) C (Ri3Ri4) -T-Rd, -L_k-TR_d, or -Lk-E;

R₈ and R₉ are each independently R_c, and R12 is R_b; or R₈ is R_c, and R₉ and R12, 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_TO;

R10. Rn&gt; R13, and R14 are each independently R_c; or R₁₀ and R13 are each independently Rc, and R11 and R14, 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 R_TO;

T and Γ are each independently selected each time they appear from link, -L_s-, -L_s-ML_s'-, or -L_s-MLs'-M'-Ls-, in which M and M 'are each independently selected each time they appear from bond, -O-, -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-, -00 (0) -, -00 (0) 0-, -C (O) N (R_b) -, -N (R_b) C (O) -, -N (R_b) C (O) O-, -OC (O) N (R_b) -, -N (R_b) S (O) -, -N (Rb) S (O)₂-, -S (O) N (R_b) -, -S (O)₂N (Rb) -, -C (O) N (Rb) C (O) -, -N (Rb) C (O) N (R_b') -, -N (R_b)SW₂N (R_b')-,

-N (R_b) S (O) N (R_b') -, carbocycle of Ο₃-Ο₁₂ or 3-12 membered heterocycle, and in which said carbocycle of C₃-C₁₂ and 3- to 12-membered heterocycle are each independently optionally substituted each time they appear with one or more R_TO;

IMPI wmuT * M «ucANo ot THE WONtDAP

INDUSTRIAL

<img file="MX346264B_D0006.tif" />

L_k is selected independently each time it appears from link, -L_S-N (R_B)CABBAGE_S'- or -L_S-C (O) N (R_B) -L_S'-; or C ^ Cg alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆₎ each of which is independently optionally substituted each time it appears with one or more R_L; or C3-C12 carbocycle or 3- to 12-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more R_TO;

E is independently selected each time it appears from carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and is independently optionally substituted each time it appears with one or more R_TO;

R_D each is independently selected each time it appears from hydrogen or R_TO;

R_TO is independently selected each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-Re, in which two R_TO Adjacent, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, may optionally form carbocycle or heterocycle;

R_B and R_b'are each independently selected each time they appear from hydrogen; or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from

<img file="MX346264B_D0007.tif" />

IMPI

INWIIVru MEXICAN

OF INDUSTRY PROPERTY!

starting from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, or carbocycle or 3-6 membered heterocycle; or 3- to 6-membered carbocycle or heterocycle; in which each 3- to 6-membered carbocycle or heterocycle in R_B or R_B'is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of C. -C₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆;

R_c is independently selected each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano; or Ο, -Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, 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; in which each 3- to 6-membered carbocycle or heterocycle in R_c is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, halogenoalkyl, -Cg, halogenoalkenyl

<img file="MX346264B_D0008.tif" />

IMPI

MltlCANO INSTITUTE

PE LA MtOPIElMD MDUSTRIAl

C₂-C₆ or halogenoalkynyl of C₂-C₆; .......

R_and is selected independently each time it appears from -OR_s, -MR_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_sRs'), -N (R_s) C (O) R_s'N (R_S) C (O) N (R_S'R_S”), -N (R_s)SW₂R_s', -SO₂N (R_sR_s'). N (Rs) SO₂N (R_s'Rs ”), -N (Rs) S (O) N (R_s'Rs ”), -OS (O) -R_s, -BEAR)₂-R_s, S (O)₂OR_s, -S (O) OR_s, -OC (O) OR_s, -N (R_s) C (O) ORs', -OC (O) N (R_sR_s'), N (Rs) S (O) -R_s', -S (O) N (R_sRs'). -P (O) (ORs)₂, or -C (O) N (R_s) C (O) -R_s'; or Οτ-Οθ alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of Ο₃-Ο₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (R_SR_S’);

R_F is independently selected each occurrence from Ci-C alkyl₁₀, C alkenyl₂-C_1st or C alkynyl₂-C₁₀, each of which contains 0, 1, 2, 3, 4, or 5 heteroatoms that are selected from O, S, or N and are independently optionally substituted with one or more R_l; or -

<img file="MX346264B_D0009.tif" />

IMPI βπτυτο MuacANo inpustuai dbumomity (Rx-Ry) Q- (Rx-Ry '), in which Q is 0, 1, 2, 3 or 4, and each R_x is independently O, S or N (R_B), in which each R_AND is independently alkylene of Ci-C₆, C alkenylene₂-C₆ or C alkynylene₂-C₆ 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 in which each R_AND'is independently C alkyl_rC₆, C alkenyl₂-C₆or C alkynyl₂-C₆ 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;

R_l is independently selected each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -SR_s, -C (O) R_S, -OC (O) R_S, -C (O) OR_S, -N (R_SR_S'). S (O) R_s, -SO₂R_s, C (O) N (R_sRs') or -N (R_S) C (O) R_S'; or carbocycle of C₃C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C- | -C haloalkyl₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; in which two R_L adjacent, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached

<img file="MX346264B_D0010.tif" />

IMPI

INSTITUI * mMUCAND

D £ LA M »Mídao INDumiAt together, may optionally form carbocycle or heterocycle;

L_s, L_s'and L_s"Are each independently selected each time they appear from link; or Ci-C alkylene₆, C alkenylene₂-C₆ or C alkynylene₂-C₆, each of which independently is optionally substituted each time it occurs with one or more R_L; Y

Rs&gt; Rs' and Rs "are each independently selected each time they appear from hydrogen; C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , -O-alkyl of Ο_ΓΟ₆, -Oalkylene CC ^ CsI-O-C ^ Ce alkyl, or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; in which each 3- to 6-membered carbocycle or heterocycle in R_s , R_s'or R_s'is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, cyanalkyl Ce, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

A and B are preferably independently selected from carbocycle of C₅-C₆ (eg phenyl), 5- to 6-membered heterocycle (eg pyridinyl or thiazolyl), or

<img file="MX346264B_D0011.tif" />

8 to 12 member bikes such as,

IMPI

ΙΝΤΠΤυΤ · M * 1CANO

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0012.tif" />

<img file="MX346264B_D0013.tif" />

Z₁ is independently selected each time it appears from O, S, NH, or CH₂, Z₂ is independently selected each time it appears from N or CH, Z₃ is independently selected each time it appears from N or CH, Z₄ is independently selected each time it appears from O, S, NH, or CH₂, and W_n W₂, W₃, W₄, W₅ and W₆ are each independently selected each time they appear from CH or N. A and B are each independently optionally substituted with one or more R_TO.

More preferably A is selected from carbocycle of C₅-C₆, 5- to 6-membered heterocycle

<img file="MX346264B_D0014.tif" />

<img file="MX346264B_D0015.tif" />

, and is optionally substituted with one or more R_TO;

B is selected from carbocycle of C₅-C₆, 5- to 6-membered heterocycle,

<img file="MX346264B_D0016.tif" />

<img file="MX346264B_D0017.tif" />

, and is optionally substituted with one or more R_TO; in which Z_1f Z₂, Z₃, Z₄, W_1t W₂, W₃,

<img file="MX346264B_D0018.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL CURRENCY

W₄, W₅, W₆ they are as defined above. Preferably Z₃ is N and Z₄ is NH. For example, A can be selected from phenyl (eg.

<img file="MX346264B_D0019.tif" />

), pyridinyl (eg.

<img file="MX346264B_D0020.tif" />

), thiazolyl (p.

<img file="MX346264B_D0021.tif" />

<img file="MX346264B_D0022.tif" />

<img file="MX346264B_D0023.tif" />

), and is optionally substituted with one or more R_TO; and B can be selected from phenyl (p.

<img file="MX346264B_D0024.tif" />

pyridinyl (eg,

<img file="MX346264B_D0025.tif" />

), thiazolyl (p.

<img file="MX346264B_D0026.tif" />

<img file="MX346264B_D0027.tif" />

), and is optionally substituted with one or more R_TO. Quite preferably both A - \ Vi and B are phenyl (eg, both A and B are * \ / '). As well

N — λ / —N i— / rather preferably, A is ⁴ \ - / * and B ^? \ = / * is; or

IMPI xsillulw M BUCANO

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0028.tif" />

<img file="MX346264B_D0029.tif" />

<img file="MX346264B_D0030.tif" />

independently is optionally substituted with one or more

Ra Also preferably, A is

<img file="MX346264B_D0031.tif" />

B is | —- N and A and B are substituted with one or more halogens, such as F or Cl. It was surprisingly discovered that when A and / or B are benzimidazole substituted with halogen (eg, A

<img file="MX346264B_D0032.tif" />

Formula I (as well as the compounds of Formulas l_TO, Ib, le, Id, Ie, I_F or I_g described below, and the compounds of each modality described thereunder) unexpectedly showed significantly improved pharmacokinetic properties, in

IMPI

1NII11U l · MEXICAN

OF coldness

INDUSTRY

<img file="MX346264B_D0033.tif" />

comparison with the same compounds but with unsubstituted benzimidazole. Improvements in pharmacokinetics can be observed, for example, as a higher total plasma level exposure, measured as the area under the curve (AUC) over a 24 hour period after oral dosing in mice. It was also surprisingly discovered that these halogen substituted benzimidazole compounds unexpectedly showed enhanced inhibitory activity against certain mutants of HCV genotype 1a (eg, the L31M, Y93H, or Y93N mutants). Accordingly, the present invention contemplates methods of using such compounds to treat HCV genotype 1a mutant infection (eg, L31M, Y93H, or Y93N mutant 1a infection). These methods comprise administering said compound to a patient having a HCV genotype 1a mutant (eg, L31M, Y93H, or Y93N mutant 1a). The present invention also contemplates the use of said compounds for the manufacture of a medicament for the treatment of a genotype 1a mutant infection (eg, L31M, Y93H, or Y93N mutant 1a infection).

Preferably D is selected from carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is optionally substituted with one or more R_TO. Preferably D can also be selected from Ci-Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, and is optionally substituted with one or more substituents selected from R_L. Of

<img file="MX346264B_D0034.tif" />

more preferably, D is carbocycle of C₅-C₆ (eg, phenyl), 5- to 6-membered heterocycle (eg, pyridinyl, pyrimidinyl, thiazolyl), or 6 to 12-membered bicycles (eg, indanyl,

IMPI

MEXICAN INSTITUTE

OF THE «ΟΛΕΟΑΟ INDUSTRIAL

4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, benzo [d] [1,3] dioxol-5-yl), and is substituted with one or more R_M, in which R_m is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-Re · Also preferably, D is phenyl, and is optionally substituted with one or more R_to. More preferably, D is phenyl, and is substituted with one or more R_m, in which R_M is how it was defined

Rm

Rn ^ T ^ Rn above. Quite preferably, D is A or

Rm

TO

T ...

UTLftfV J in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they can also be preferably halogen such as F.

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

I

IMPI

INSTmn * MEXICA N &lt;;

Oí LA FROFIEDAI »INDUSTRIAL

<img file="MX346264B_D0035.tif" />

<img file="MX346264B_D0036.tif" />

JWV, WW, or WW, in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more Rn may also preferably be halogen such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, and is optionally substituted with one or more R_TO. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, or benzo [d] [1,3] dioxol-5-yl, and is substituted with one or more R_M. Rather preferably, D is

<img file="MX346264B_D0037.tif" />

optionally substituted with one or more R_M.

Preferably R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CrCe alkyl C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or heterocycle of

<img file="MX346264B_D0038.tif" />

IMPI

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL to 6 members, each of which independently is optionally substituted each time it appears with one or more substituents that are selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or C ^ Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, or carboxy. Rather preferably, R_M is CrCe alkyl 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_AND, in which L_s is a Ci-C bond or alkylene₆, and R_and is -N (R_SR_S'), -OR_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)SW₂R_s', -SO₂R_s, -MR_s, or -P (O) (OR_s) 2, ®n which R_s and Rs' can be selected, for example, each independently each occurrence from (1) hydrogen or (2) C ^ Cg alkyl optionally substituted each occurrence with one or more halogen, hydroxy, - O-Ci-Cg alkyl or 3-6 membered heterocycle; or Rm is C ^ Cg alkyl,

<img file="MX346264B_D0039.tif" />

IMPI

ΙΝ5ΤΓΓΌΤ MBUCANO M the currency INC ISTMIA L alkenyl of C₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, halogenoalkyl of geno ^ ,β, halogenoalkenyl of C₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (R_sRs') More preferably, R_M is halogen (for example fluoro, chloro, bromine, iodine), hydroxy, mercapto, amino, carboxy, or C-Ce alkyl (for example, methyl, isopropyl, tert-butyl), C-alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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_s-Re in which L_s is a link and R_AND is -N (R_sRs'). -OR_s, -N (Rs) C (O) ORs', -N (R_s)SW₂R_s', -SO₂Rs, or -SR_s. For example in cases where L_s is a link, R_AND is -N (alkyl (C₁-C₆))₂ (for example, -NMe₂); -N (alkylene (C₁-C_and) -O-alkyl (C₁-C₆))₂ (for example -N (CH₂CH₂OMe)₂); -N (alkyl (C₁-C₆) (rent (C₁-C₅) -O-alkyl of

LMpi • wmyroMuucANo

WUIBOFISDad industrial

<img file="MX346264B_D0040.tif" />

Ci-C₆) (for example -N (CH₃) (CH₂CH₂OMe)); -O-C, -C alkyl₆ (for example, -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -On-hexyl); -O-C ^ Cs halogenoalkyl (for example, -OCF₃, -OCH₂CF₃); -O-alkyleneiCi-Cej-piperidine (for example, -O-CH₂CH₂-1 -piperidyl); -N (alkyl (Ci-C₆)) C (O) O-Ci-C alkyl₆ (for example, -N (CH₃) C (O) OCH₂CH (CH₃)₂), -N ((C₁-C₆))-SW₂-C- | -C alkyl₆ (for example, -N (CH₃)SW₂CH₃); -SW₂-C ^ Ce alkyl (for example, -SO₂I); -SW₂-halogenoalkyl of CrCe (for example, -SO₂CF₃); or -S-C ^ Cg halogenoalkyl (for example, SCF₃). Also preferably R_M is -L_S-R_AND in which L_s is C alkylene_rC₆ (for example, ^-CH2-, -C (CH3) 2 ·, -C (CH3) 2-CH2-) and RE is -O-Rs, ^-C (O) ORs, -N (RS) C (O) OR_S', or -P (O) (OR_s) 2 For example R_M is -alkylene-Cg) OR_s (for example, -C (CH₃)₂-CH₂-OMe); -alkylene (C₁-C₆) -C (O) OR_s(for example, -C (CH₃)₂-C (O) OMe); -alkylene (C₁-C₆) -N (R_s) C (O) OR_s'(for example, -C (CH₃)₂-CH₂-NHC (O) OCH₃); or -alkylene (Ci-C₆) P (O) (OR_s)₂ (for example, -CH₂-P (O) (OEt)₂). Also more preferably R_M is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (R_SR_S'). For example R_M is cycloalkyl (e.g. cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl

<img file="MX346264B_D0041.tif" />

IMPI

M MUCAMO INSTITUTE OF INDUSTRIAL PROPERTY (for example, morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, 4-methoxycarbon¡lp¡perazin-1-lio, pyrrolidin-1 -yl, piperidin-1-yl, 4-methylpiperidin-1-lio, 3,5-d¡methylpiper¡din-1-yl, 4,4difluoropiperidin-1-yl, tetrahydropyran-4 -yl, pyrldinyl, pyridin-3-yl, 6 (dimethylamino) pyridin-3-it). Rather preferably, R_M is C ^ Ce alkyl 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 carbocycle of C₅-C₆₁5- to 6-membered heterocycle or 6 to 12-membered bicyclo and is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, in which said carbocycle of C₃-C₆ or 3-6 membered heterocycle independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of Ct-Cs, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (RsRs'), and J may also be optionally substituted with one or more R_to. Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of

<img file="MX346264B_D0042.tif" />

IMPI

MEXICAN INSTITUTE

OF THE PROHIJAD industriai

C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably, J is at least substituted with one carbocycle of C₃-C₆ 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-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'). Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is 6 to 12 membered bicycles (for example, a fused 7 to 12 membered bicycles, bridged or spiro structure comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_TO. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ 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-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-Ce halogenoalkyl,

<img file="MX346264B_D0043.tif" />

IMPI

INSTITUTO MEXICANO onAnontDA »INWSTMAL halogenoalkenyl C₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

J í1

YR_n

-N (R_SR_S'). Quite preferably, D is, in which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

J Rn. TO .^rn rZ γ Rn

-N (RsRs') · Also preferably, D is X, in which each R_n is independently selected from R_D and preferably it is hydrogen or halogen, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which is independently optionally substituted with one or more

IMPI nviliwu MEXICAN

MWJKMML

Industrial

<img file="MX346264B_D0044.tif" />

substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CrCe, alkenyl of C₂-C₆, C alkynyl₂-C₆, C-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs')&gt; YJ may also be optionally substituted with one or more R_TO. Also from

J preference, D is, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C alkenyl alkyl₂-C₆, alkynyl

C₂-C₆, C ^ -Ce haloalkyl, C haloalkenyl₂-C₆₁C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs')

It was surprisingly discovered that when D contains a halogen-substituted carbocycle or heterocycle (e.g., a halogen-substituted 5-6 membered carbocycle or heterocycle directly linked to X), the compound of Formula I (as well as the compounds of Formulas l_TO, l_B, le, Id, Ie, If or I_g described below, and the compounds of each modality described under the

<img file="MX346264B_D0045.tif" />

IMPI

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL themselves) may exhibit significantly improved inhibitory activity against HCV genotypes 2a, 2b, 3a or 4a and / or improved pharmacokinetic properties. Therefore, the present invention contemplates methods of using said compounds to treat infection with HCV genotype 2a, 2b, 3a or 4a. These methods comprise administering said compound to a patient having HCV genotype 2a, 2b, 3a or 4a. The present invention also contemplates the use of said compounds for the manufacture of a medicament for the treatment of HCV genotypes 2a, 2b, 3a or 4a. The appropriate D for this purpose may be, for

<img file="MX346264B_D0046.tif" />

example, .Jw or Jw as described above, in which at least one R_N it is halogen such as fluorine. Specific examples of appropriate D include, but are not limited to

<img file="MX346264B_D0047.tif" />

IMPI

INSTITUTO MEXICANO Dt LA HtOHEDAD INDUSTRIAL

<img file="MX346264B_D0048.tif" />

they are as described above.

X is preferably carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is optionally substituted with one or more R_TO or R_F. X can also be carbocycle of C₅-C₆ or 5- to 6-membered heterocycle which is optionally substituted with one or more R_TO or R_F, in which two R_TO Adjacent in X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. Also preferably, X is

<img file="MX346264B_D0049.tif" />

in which

X₃ is C (H) or preferably N and is directly appended to -L₃-D;

X4 is C alkylene₂-C₄, C alkenylene₂-C₄ or alkynylene from

C₂-C₄, 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_TO or R_F, and two R_TOAdjacent in X, taken together with the ring atoms to which they are attached, may optionally form a 5- to 6-membered carbocycle or heterocycle. Also, X can be

IMPI

7 mexican institute

<img file="MX346264B_D0050.tif" />

directly linked to -L₃-D, X₄ is C alkylene₂-C₄, alkenylene

C₂-C₄ or C alkynylene₂-C₄ 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_TO or R_F, and two R_to Adjacent in X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. Likewise, X can be

<img file="MX346264B_D0051.tif" />

which N is directly linked to L₃-D, X₄ is C alkylene₂-C₄, C alkenylene₂-C₄ or C alkynylene₂-C₄ 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_to or R_F, and two R_to Adjacent in X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

<img file="MX346264B_D0052.tif" />

^X3,

For example, X can be χ ^ χ₁

X₂= X₂

IMPI mexican institute of property

INDUSTRY!

<img file="MX346264B_D0053.tif" />

<img file="MX346264B_D0054.tif" />

Independent is independently selected each time it appears from CH₂, O, S or NH, X₂ is independently selected each time it appears 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_TO or

R_F, and two R_to adjacent in X, taken together with the ring atoms to which they are attached, optionally form a carbocycle

<img file="MX346264B_D0055.tif" />

Xu / X!

or 5- to 6-membered heterocycle. For another example, X is X!

U V w*

<img file="MX346264B_D0056.tif" />

^ΧΚν ^^Χ2 X2

<img file="MX346264B_D0057.tif" />

<img file="MX346264B_D0058.tif" />

<img file="MX346264B_D0059.tif" />

<img file="MX346264B_D0060.tif" />

<img file="MX346264B_D0061.tif" />

<img file="MX346264B_D0062.tif" />

Xix ^ X₂x₂

<img file="MX346264B_D0063.tif" />

<img file="MX346264B_D0064.tif" />

JVUV *

<img file="MX346264B_D0065.tif" />

<img file="MX346264B_D0066.tif" />

<img file="MX346264B_D0067.tif" />

IMPI

INSTITUTO MEXICANO M LA HlOMEDAIj INDUSTWUÍ / γ^χγλ / γ^χγΑ

X- | ^ ^^ 2 Y2 &lt;s / Xl

X₂ or X₂ , in which Xi is independently selected each time it appears from CH₂, O, S or NH, X₂is independently selected each time it appears 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 in which X is optionally substituted with one or more R_to or R_F, and two R_TOAdjacent in X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

Preferably, X is jvVv

<img file="MX346264B_D0068.tif" />

<img file="MX346264B_D0069.tif" />

in which X₃ is C (H) or N and is directly linked to -L₃-D, X₃'is C and is directly linked to

-L₃-D, and in which X is optionally substituted with one or more

R_TO or R_F, and two R_to Adjacent in 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:

<img file="MX346264B_D0070.tif" />

<img file="MX346264B_D0071.tif" />

in which it is indicated by the covalent bond to -L₃-D. Each X can be optionally substituted with one or more R_TO or R_F, and two R_TOAdjacent in 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_TO or R_F:

<img file="MX346264B_D0072.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRY PROPERTY!

<img file="MX346264B_D0073.tif" />

As shown, the relative stereochemistry at positions 2 and 5 of the pyrrolidine ring above can be either cis or trans. The stereochemistry of the R substituents_TO Optional positions 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 can 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_TO or R_F:

<img file="MX346264B_D0074.tif" />

<img file="MX346264B_D0075.tif" />

<img file="MX346264B_D0076.tif" />

<img file="MX346264B_D0077.tif" />

<img file="MX346264B_D0078.tif" />

As shown, the relative stereochemistry at the 3 and 5 positions of the thiomorpholine ring can be either cis or trans.

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Depending on the particular substituents attached to thiomorpholine, the stereochemistry at any carbon can be either (R) or (S). I

Also preferably, X is '---' or ® —'J in which in which X₃ is N and is directly linked to -L₃D, and X is optionally substituted with one or more R_TO or R_F. Preferably R_F is C1-C10 alkyl, C alkenyl₂-C₁₀ or C alkynyl₂-Cio, each of which contains 0, 1, 2, 3, 4, or 5 heteroatoms that are selected from O, S, or N and is independently optionally substituted with one or more substituents that are selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano. Also preferably, R_F is Ci-C alkyl₁₀, C alkenyl₂-Cio or C alkynyl₂-C₁₀, each of which contains 0, 1, 2, 3, 4, or 5 O and is independently optionally substituted with one or more RL. Also preferably, R_F is - (R_xRy) Q- (Rx-Ry '), in which Q is 0, 1, 2, 3 or 4; each R_x is independently O, S or N (R_B); each R_AND is independently alkylene of C_rC_6: C alkenylene₂-C₆ or C alkynylene₂-C₆ each of which is independently optionally substituted with one or more substituents selected from

IMPI institute mmcanc delarhomídai

INDUSTRIE '

<img file="MX346264B_D0079.tif" />

halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano; and each R_AND'is independently C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂C₆ 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_TO or R_F, each R_F is independently selected from CpCio alkyl, C alkenyl₂-C₁₀ or C alkynyl₂-C₁₀, 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_TO or R_F, each R_F is independently selected from - (O-Ci-C alkyl C ^ CejjQ-CO-C₆), in which Q is preferably 0, 1, 2 or 3.

Lt and L₂ preferably they are independently Ci-C bond or alkylene₆, L₃ preferably selected from bond, C ^ Ce or -C (O) - alkylene, and L_1t L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_n L₂ and L₃ are each independently bond or alkylene of C ^ Ce (e.g., -CH₂- or -CH2CH2-), and are each independently optionally

<img file="MX346264B_D0080.tif" />

IMPI

INSTITUTO MEXICANO DE LA PRONIDAD INDUSTRIAL replaced with one or more R_L. Rather preferably, L-ι, L₂ and L₃ they are link.

And preferably it is selected from

-Ls-C ^ R ^ NCRsbT-RD, -L_S-C (R₃R₄) C (R₆R₇) -TR_D, -6-0 ^^) 1 ^ 5) -7R_D, -GC (R₃R₄) C (R₆R₇) -TR_D, -N (R_b) C (O) C (R₁R₂) N (R₅) -TR_d,

-N (R_b) C (O) C (R₃R₄) C (R_sR₇) -TR_d, -C (O) N (R_b) C (Ri R₂) N (R₅) -TR_d,

-C (O) N (Rb) C (R₃R₄) C (R₆R₇) -TR_d, -N (Rb) C (O) -L_s-E, or -C (O) N (Rb) -L_sE. G is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, such

<img file="MX346264B_D0081.tif" />

optionally substituted with one or more R_to (for example, one or more chlorine or bromine). E is preferably a 7 to 12 membered bike (such as

A vv ° as Z₂oU in _and| _what| (j_{I know} independently selects each time appearing from - (CH₂) - or - (NH) -; V and Z₂or are each independently selected from alkylene of θ! -θ₄, C alkenylene₂-C₄ or C alkynylene₂-C₄₎ in which at least one carbon atom may independently be optionally replaced with O, S, or N), and is independently optionally substituted with one or more R_TO. More preferably, Rt is R_c, and R2 and R5. Taken together with the atoms to which they are attached, they form a heterocycle of 5 to

<img file="MX346264B_D0082.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0083.tif" />

<img file="MX346264B_D0084.tif" />

which is optionally substituted with one or more R_TO (such as, but not limited to, hydroxy. halogen (eg, fluoro), Ci-C alkyl₆ (eg, methyl), or C alkenyl₂-C₆ (eg, allyl)); and R₃ and R₆ 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 carbocycle / heterocycle or 6 to 12-membered bicyclo (for example,

<img file="MX346264B_D0085.tif" />

<img file="MX346264B_D0086.tif" />

which is optionally substituted with one or more R_TO (such as, but not limited to, hydroxy, halogen (eg, fluoro), CpCe alkyl (eg, methyl), or C alkenyl₂-C₆ (eg allyl)).

And you can also select from -M-

<img file="MX346264B_D0087.tif" />

IMPI

INSTITUTO MMcicano or »la prome» ao industrial

C (R₁R₂) N (R₅)-CABBAGE_Y'-M'-R_d, -MC (RiR₂) N (R₅) -L_Y^,-M'-R_d, -L_sC (R₁R₂) N (R₅)-CABBAGE_Y'-M'-R_d, -L_s-C (R₁R₂) N (R₅) -L_Y'-M'-Rd, -MC (R₃R₄) C (R₆R₇) -C (O) -Ly'-M'-R_d, -MC (R₃R₄) C (R₆R₇) -Ly'-M'-R_d, -l_sC (R₃R₄) C (R₆R₇) -C (O) -Ly'-M'-Rd, O -L_s-C (R₃R₄) C (R₆R₇) -L_Y'-M'-R_d, in which M is preferably bond, -C (O) N (R_b) - or -N (R_b) C (O) -, M 'is preferably bond, -C (O) N (R_B) -, -N (R_B) C (O) -, -N (R_B) C (O) O-, N (R_b) C (O) N (R_b') -, -N (R_b) S (O) - or -N (R_b)SW)₂-, and L_AND'is preferably C &lt;-C alkylene_s which is optionally substituted with one or more R_l L_Y'For example, it is a C ^ Ce alkylene such as, but

<img file="MX346264B_D0088.tif" />

and the R_l Optional is a substituent such as, but not limited to, phenyl, -SMe, or methoxy. Any stereochemistry on a carbon within group L_AND'can be either (R) or (S). More preferably, R-ι is R_c, and R₂ and Rs, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle

<img file="MX346264B_D0089.tif" />

which is optionally substituted with one or more R_TO (for example, one or more hydroxy); and R₃ and R₆ 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 bicyclo

IMPI

MEXICAN INSTITUTE

OF INDUSTRY PROPERTY!

<img file="MX346264B_D0090.tif" />

optionally substituted with one or more R_TO.

Also preferably, Y is selected from

-NíRBjCO-CíR ^ NÍRshCÍOJ-LY'-NÍRBlCíOIO-RD, -N (R_B) COC (RiR2) N (R₅)-CABBAGE_Y'-N (Rb) C (O) -Rd, -NÍReJCO-CíR ^ NCRehCÍO) L_Y'-N (R_b)SW)₂-R_d, -N (R_b) CO-C (R₁R₂) N (R₅) -C (O) -Ly'-N (R_bR_b') -R_d, -N (R_b) CO-C (R₁R₂) N (R₅) -C (O) -Ly'-OR_d, -N (R_b) CO-C (RiR₂) N (R₅)CABBAGE_Y'-R_d, -N (R_b) CO-C (R₁R₂) N (R₅) -R_d, -L_s-C (R₁R₂) N (R₅)-CABBAGE_Y'N (R_b) C (O) OR_d, -L_s-C (R₁R₂) N (R₅)-CABBAGE_Y^,-N (R_b) C (O) -R_d, -l_sCíR ^ JNCRshCíOJ-LY'-NíRBjSÍOh-RD, -Ι_8-Ο ^^₂) Ν ^₅) -Ο (Ο) -Ι-γ'N (R_bRb ') - Rd, -Ls-CíR ^ JNÍRsJ-CÍOÍ-Ly'-O-Rd, -Ls-CÍR ^ JNíRs) C (O) -L_Y'-Rd, -L_s-C (R₁R₂) N (R₅) -R_DJ -N (R_b) CO-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (R_b) C (O) O-Rd, -N (R_b) CO-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (Rb) C (O) Rd, -N (R_b) CO-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (R_b)SW)₂-Rd, -N (Rb) COC (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (R_bRb ') - Rd, -N (Rb) CO-C (R₃R₄) C (R₆R₇)CABBAGE_Y'-OR_d, -N (R_b) CO-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-R_d, -N (R_b) COC (R₃R₄) C (R_sR₇) -Rd, -L_s-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (R_b) C (O) OR_d, -L_s-C (R₃R₄) C (R6R₇)-CABBAGE_Y'-N (Rb) C (O) -R_d&gt; -Ls-C (R₃R₄) C (R₆R₇)CABBAGE_Y'-N (R_b)SW)₂-R_d, -Ls-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-N (R_bRb ') - Rd,

-Ls-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-OR_d, -L_s-C (R₃R₄) C (R₆R₇)-CABBAGE_Y'-R_d, or -Ls-C (R₃R₄) C (R₆R₇) -Rd, in which L_AND'preferably is Ci-C alkylene₆ which is optionally substituted with one or more R_l. Ri can be R_c, and R₂ and R5, taken together with the atoms a

<img file="MX346264B_D0091.tif" />

which these are united, can form a heterocycle of 5 to 6

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0092.tif" />

) which is optionally substituted with one or more R_TO; and R3 and Re can each be independently R_c, and R₄and R₇, taken together with the atoms to which they are attached, can form a 5- to 6-membered carbocycle / heterocycle or 6 to 12-membered bicyclo (e.g., o * ^) which is optionally substituted with one or more R_TOQuite preferably, Y is selected from -N (R_b”) CO-C (R₁R₂) N (R₅) -C (O) -Ly-N (Rb ”) C (O) -Ls-Re or -CCR ^ zjNÍRs) C (O) -L_Y-N (R_b")CABBAGE_s-Re, or Y is -GC (R₁R₂) N (R₅)-CABBAGE_ANDN (R_b")CABBAGE_s-Re, in which L_AND is C alkylene_rC₆ optionally substituted with one or more R_L, and Rb "is each independently R_B. R_B"And Ri are each preferably hydrogen or Ci-Ce alkyl, and R₂ and Rs. taken together with the atoms to which they are attached, preferably form a heterocycle of 5

IMPI

INSTITUTO M &amp; X1CANO DB LA HIOHBDAD INDUSTRIAL to 6 members or bicycles of 6 to 12 members (for example,) which is optionally substituted with one or more R_TO (such as, but not limited to, hydroxy, halogen (eg, fluoro), Ci-C alkyl₆ (eg, methyl), or C alkenyl₂-C₆ (eg allyl)). Preferably, L_AND is Ci-Ce alkylene substituted with one or more R_L such as a carbocycle of C₃-C₆ 3 to 6 membered heterocycle which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CtCs, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. Rather preferably, L_AND is a C - C alkylene₆ such as, but not limited to, (the stereochemistry at a carbon within the L group_AND can be either (R) or (S)), L_AND by way of

<img file="MX346264B_D0093.tif" />

independently is optionally substituted with one or more R_L (by

IMPI

INSTITUTO MEXICANO DE ΙΛ PROriEDAD INDUSTRIAL example, one or more phenyl or methoxy), G preferably is

<img file="MX346264B_D0094.tif" />

<img file="MX346264B_D0095.tif" />

R_b"Is hydrogen; -C (R₁R₂) N (R₅) - is ΛΛ / V *; L_s is a link; and R_AND it is methoxy.

Non-limiting examples of preferred Y include:

<img file="MX346264B_D0096.tif" />

<img file="MX346264B_D0097.tif" />

<img file="MX346264B_D0098.tif" />

<img file="MX346264B_D0099.tif" />

<img file="MX346264B_D0100.tif" />

<img file="MX346264B_D0101.tif" />

HN- /

<img file="MX346264B_D0102.tif" />

<img file="MX346264B_D0103.tif" />

<img file="MX346264B_D0104.tif" />

<img file="MX346264B_D0105.tif" />

<img file="MX346264B_D0106.tif" />

<img file="MX346264B_D0107.tif" />

<img file="MX346264B_D0108.tif" />

<img file="MX346264B_D0109.tif" />

<img file="MX346264B_D0110.tif" />

<img file="MX346264B_D0111.tif" />

<img file="MX346264B_D0112.tif" />

<img file="MX346264B_D0113.tif" />

<img file="MX346264B_D0114.tif" />

<img file="MX346264B_D0115.tif" />

IMPI

INSTITUTE ΜLX1CAN

Say THE inbüstmial nOHCDAD or_d--T ' _t in which T and R_D they are as defined in the present application. T, for example, can be -L_s-ML_s'-M'-Ls ”- in which L_s is a link; M is C (O); L_s'is alkylene of Ο_ΓΟ₃ such as,

<img file="MX346264B_D0116.tif" />

I, in which L_s'independently is 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 link. Any stereochemistry on a carbon within group L_s'can be either (R) or (S). R_D, for example it is methoxy. TR_D It includes,

<img file="MX346264B_D0117.tif" />

<img file="MX346264B_D0118.tif" />

TR_D can also include certain stereochemical configurations

IMPI iwyrnuTOMtMCANO OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0119.tif" />

therefore T-Ro includes, but is not limited to

<img file="MX346264B_D0120.tif" />

Non-limiting examples of preferred Y also include:

<img file="MX346264B_D0121.tif" />

<img file="MX346264B_D0122.tif" />

<img file="MX346264B_D0123.tif" />

C (R₈R₉) N (R₁₂) -TR_D, -Ls-C (R₁oRn) C (R₁₃R₁4) -T-RD, -GC (R₈R₉) N (R₁₂) TR_d, -GC (R₁₀Rii) C (R₁₃Ri4) -TR_D, -N (R_b) C (O) C (R₈R₉) N (R₁₂) -TR_D1

-N (R_b) C (0) C (R₁oRii) C (R₁₃Ri4) -T-Rd, -C (O) N (R_b) C (R₈R₉) N (R₁₂) -TR_d,

-C (O) N (R_b) C (R₁₀Rii) C (R₁₃Ri4) -T-Rd. -N (R_b)CABBAGE_s-E, or -C (O) N (R_b) L_s-AND. G is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, such

<img file="MX346264B_D0124.tif" />

Ra (for example, one or more

<img file="MX346264B_D0125.tif" />

optionally substituted with one or more

E is preferably an 8 to 12 membered bicycles (chlorine or bromine).

<img file="MX346264B_D0126.tif" />

in which U is independently selected each time it appears from - (CH₂) - or - (NH) -¡ and V

<img file="MX346264B_D0127.tif" />

and Z₂or are each independently selected from Ci-C alkylene₄, C alkenylene₂-C₄ or C alkynylene₂-C₄, in which at least one carbon atom independently

IMPI

IHSTTTUTO MEXICANO DE LA PROPERTY INDUSTRIAL is optionally replaced with O, S or N), and independently is optionally substituted with one or more R_TO. More preferably, R₈ is R_c, and R₉ and Ri₂&gt; taken together with the atoms to which they are attached, they form a 5 to 5 heterocycle

<img file="MX346264B_D0128.tif" />

<img file="MX346264B_D0129.tif" />

(such as, but not limited to, hydroxy, halogen (eg, fluoro), Ci-C alkyl₆ (eg, methyl), or C alkenyl₂-C₆ (eg, allyl)); and R₁₀ and R13 are each independently Rc, and R11 and Rn, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle / heterocycle or

<img file="MX346264B_D0130.tif" />

<img file="MX346264B_D0131.tif" />

IMPI

INSTITUTO MEXICANO DE LA PW1EDAP INDUSTRIAL bicycle from 6 to 12 members (for example,

<img file="MX346264B_D0132.tif" />

which is optionally substituted with one or more R_TO (such as, but not limited to, hydroxy, halogen (eg, fluoro), Cy-Cealkyl (eg, methyl), or C-alkenyl₂-C₆ (eg allyl)).

Z can also be selected from

-MC (R₈R₉) N (R₁₂) -C (O) -Ly'-M'-Rd, -MC (R₈R₉) N (R₁₂) -L_Y'-M'-R_d,

-L_s-C (R₈R₉) N (R₁₂) -C (O) -Ly'-M'-R_d, -L_s-C (R₈R₉) N (R₁₂) -L_Y'-M'-R_d,

-MC (RiqRi i) C (Ri₈Ri4) -C (O) -Ly'-M'-Rd, -MC (RioRi i) C (Ri₃Ri4) -Ly'-M'Rd, -Ls-C (R₁₀Ri i) C (R- |₃R₁₄) -C (O) -Ly'-M'-Rd, or -Ls-C (RioRii) D (Ri3Ri₄)^_Ly'-M'-R_d, in which M is preferably bond, -C (O) N (R_B) - or -N (R_b) C (O) -, M 'is preferably bond, -C (O) N (R_B) -, -N (R_B)CO)-,

-N (R_b) C (O) O-, N (R_b) C (O) N (R_b') -, -N (R_b) S (O) - or -N (R_b)SW)₂-, and L_AND'preferably is Ci-C alkylene₆ which independently is optionally substituted with one or more R_L. L_AND', for example, is a C! -C alkylene₆ such as, but not limited to,

<img file="MX346264B_D0133.tif" />

<img file="MX346264B_D0134.tif" />

substituent such as, but not limited to, phenyl, -SMe, or methoxy. Any stereochemistry on a carbon within group L_AND'can be either (R) or (S). More preferably, R₈ is R_c, and Rs and Ri2,

<img file="MX346264B_D0135.tif" />

IMPI

INSTITUTO MEXICANO DE LA PROPIEDAD inbustrial taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6 to 12-membered bicyclo (for example, X o) which is optionally substituted with one or more R_TO (for example, one or more hydroxy); and Rw and R13 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 carbocycle / heterocycle or 6-membered bicyclo (e.g., o) which is optionally substituted with one or more R_TO.

Also preferably, Z is selected from -N (R_b) CO-C (R₈R₉) N (R₁₂)-CABBAGE_Y'-N (Rb) C (O) OR_d, -N (R_b) COC (R₈R₉) N (Ri₂)-CABBAGE_Y'-N (R_b) C (O) -R_d, -N (R_b) CO-C (R₈R₉) N (R₁₂)CABBAGE_Y'-N (R_b)SW)₂-R_d, -N (Rb) CO-C (R₈R₉) N (R₁₂) -C (O) -Ly'-N (R_bR_b') Rd, -N (R_b) CO-C (R₈R₉) N (R₁₂)-CABBAGE_Y'-OR_d, -N (R_b) COC (R₈R₉) N (R₁₂) -C (O) -Ly'-R_d, -N (R_b) CO-C (R₈R₉) N (R₁₂) -R_d, -LsC (R₈R₉) N (Ri₂)-CABBAGE_Y'-N (R_b) C (O) OR_d, -L_s-C (R₈R₉) N (R₁₂) -C (O) -L.y'N (Rb) C (O) -R_d, -L_s-C (R₈R₉) N (R₁₂) -C (O) -Ly'-N (R_b)SW)₂-R_d, -L_sC (R₈R₉) N (R₁₂)-CABBAGE_Y'-N (R_bR_b') -R_d, -Ls-C (R₈R₉) N (R₁₂)-CABBAGE_Y'-OR_d, -L_s-C (R₈R₉) N (R₁₂) -C (O) -Ly'-R_d, -Ls-C (R₈R₉) N (R₁₂) -R_d,

-NtRBjCO-CÍRwRiOCíR ^ R ^ -CtCO-LY'-NÍRBjCÍCOO-RD, -N (R_b) COOKwRujCíR ^ RuJ-CíOj-LY'-NÍRBjCíOJ-Ro, -N (R_b) COIMPI Mexican Institute of NoncoAD

INDUSTRIAL

-N (R_b) CO-N (R_b) CO48

C (R₁₀Ri₁) C (R₁₃R₁₄) -C (O) -Ly'-N (R_b)SW)₂-R_D1C (R₁₀R₁₁) C (R₁₃R₁4) -C (O) -L_Y'-N (R_bR_b') -R_d,

C (Ri₀Rii) C (Ri₃Ri₄) -C (O) -Ly'-OR_d, -N (R_b) CO-C (R₁₀Ri i) C (R₁₃R₁₄) C (O) -Ly'-R_d, -N (R_b) CO-C (R₁₀R₁₁) C (R₁₃R₁₄) -R_d, -LsC (R₁₀Rii) C (R₁₃R₁₄) -C (O) -Ly'-N (R_b) C (O) OR_d&gt; -Ls-C (R₁₀Rii) C (R₁₃R₁₄) C (O) -Ly'-N (R_b) C (O) -R_d, -L_s-C (R₁₀Rii) C (R₁₃R₁4) -C (O) -Ly'-N (Rb) S (O)₂R_d, -Ls-CíR ^ RnjCCR ^ R ^ j-CCOJ-LY'-NÍRBRB'j-RD, -L_sC (RioRh) C (Ri₃Ri₄) -C (0) -Ly'-0-Rd, -L_s-C (R₁₀Rii) C (R₁₃R₁₄) -C (O) -Ly'R_d, or -L_s-C (Ri₀Rii) C (R₁₃R₁₄) -R_d, in which L_AND'is preferably C alkylene_rC₆ which independently is optionally substituted with one or more R_L. R_s can be_c, and Rg and R₁₂, taken together with the atoms to which they are attached, can form a 5 to 6 membered heterocycle or 6 to 12 bicycles

<img file="MX346264B_D0136.tif" />

optionally substituted with one or more R_TO; and Rio and R13 can each be independently R_c, and Rn and Ri₄, taken together with the atoms to which they are attached, can form a 5- to 6-membered carbocycle / heterocycle or 6 to 12-membered bicyclo (for example, substituted with one or more R_TO.

<img file="MX346264B_D0137.tif" />

<img file="MX346264B_D0138.tif" />

) which is optionally

IMPI ι «πττυτο Mexican

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0139.tif" />

Quite preferably, Z is selected from

-N (Rb ") CO-C (R₈R₉) N (R₁₂)-CABBAGE_Y-N (R_b)CABBAGE_s-Convict

-C (R₈R₉) N (R₁₂)-CABBAGE_Y-N (R_b")CABBAGE_s-Re, or Z is -GC (R₈R₉) N (R₁₂)CABBAGE_AND-N (R_B")CABBAGE_S-R_AND, in which L_AND is Ο, -Οθ alkylene optionally substituted with one or more R_L, and Rb "is each independently R_B. Rb "and Rs are each preferably hydrogen or C-C alkyl₆, and

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 bicyclo (for example,

<img file="MX346264B_D0140.tif" />

or

<img file="MX346264B_D0141.tif" />

) which is optionally substituted with one or more R_to (such as, but not limited to, hydroxy, halogen (e.g. fluoro), C ^ -Ce alkyl (e.g. methyl), or C alkenyl₂-C₆ (eg allyl)). Preferably, L_AND is C ^ Ce alkylene substituted with one or more R_L such as a carbocycle of C₃-C₆ 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl C ^ Ce, C alkenyl₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_rC₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. Rather preferably, L_AND is a

<img file="MX346264B_D0142.tif" />

IMPI «ΜΠίτυτο mukan ·

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0143.tif" />

<img file="MX346264B_D0144.tif" />

C-Ce alkylene such as, but not limited to,

<img file="MX346264B_D0145.tif" />

from group L_AND can be either (R) or (S)); L_AND independently is optionally substituted with one or more R_L (for example, one or H

........... κ^νή .......

plus phenyl or methoxy); G preferably is! Rb^is hydrogen;

<img file="MX346264B_D0146.tif" />

-C (R₈R9) N (R₁₂) - is JU; L_s is a link; and R_AND it is methoxy.

Non-limiting examples of preferred Z include:

<img file="MX346264B_D0147.tif" />

<img file="MX346264B_D0148.tif" />

PH

<img file="MX346264B_D0149.tif" />

<img file="MX346264B_D0150.tif" />

<img file="MX346264B_D0151.tif" />

<img file="MX346264B_D0152.tif" />

<img file="MX346264B_D0153.tif" />

<img file="MX346264B_D0154.tif" />

HO

<img file="MX346264B_D0155.tif" />

<img file="MX346264B_D0156.tif" />

^ NH ^T^ Rd, ^t'-r_Gave

<img file="MX346264B_D0157.tif" />

<img file="MX346264B_D0158.tif" />

IMPI

I1WTUT9 MflUCANQ! H THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0159.tif" />

<img file="MX346264B_D0160.tif" />

<img file="MX346264B_D0161.tif" />

<img file="MX346264B_D0162.tif" />

° v / γ-ΝΗ

<img file="MX346264B_D0163.tif" />

°\ / \ %·· \ &gt;

N

V-NH | ^TRd, η-Α, λΗ

N

V-NH | '^T-Ro.

<img file="MX346264B_D0164.tif" />

in which T and R_D they are as defined in the present application. T, for example, can be -L_s-ML_s'-M'-Ls ”- in which L_s is a link; M is C (O); L_s'is CpCe alkylene such as,

<img file="MX346264B_D0165.tif" />

<img file="MX346264B_D0166.tif" />

, in which L_s'independently is optionally substituted with one or more R_L; the R_L optional is a substituent such as, but not limited to, phenyl or methoxy; M 'is -NHC (O) - or

-NMeC (O) -; and L_s”Is a link. Any stereochemistry on a carbon within group L_s'can be either (R) or (S). R_D, for example it is methoxy. TR_D includes, but is not limited to:

impi &lt;&gt; n * vro Muicano M la nentoAD

<img file="MX346264B_D0167.tif" />

it can include certain stereochemical configurations; Thus

TR_d includes, but is not limited to:

<img file="MX346264B_D0168.tif" />

/ WW *

<img file="MX346264B_D0169.tif" />

<img file="MX346264B_D0170.tif" />

<img file="MX346264B_D0171.tif" />

<img file="MX346264B_D0172.tif" />

include:

Non-limiting examples of Z preferred also

<img file="MX346264B_D0173.tif" />

IMPI

UWmVTOMatCANO otunonuA »INDUSTRY!

<img file="MX346264B_D0174.tif" />

T can be selected, without limitation, independently each time it appears from -C (O) -L_S'-, -C (O) OL_S'-, -C (O) -Ls'-N (Rb) C (O) -L_s”-, -C (O) -L_s'-N (R_b) C (O) OL_s”-, -N (R_b)CABBAGE_s'-N (R_b)CABBAGE_s”-, -N (R_b)CABBAGE_s'-N (R_b) C (O) OL_s”-, or -N (R_b)CABBAGE_s'-N (R_b) -L_s”-. Preferably, T is independently selected each time it appears from -C (O) -Ls'-M'L_s”- or -N (R_b)CABBAGE_s'-M'-L_s”-. More preferably, T is independently selected each occurrence from -C (O) -Ls'-N (R_b)CABBAGE_s”- or -C (O) -L_s'-N (R_b) C (O) OL_s”-.

<img file="MX346264B_D0175.tif" />

IMPI

T can also be, for example, -Ls-ML_s'-M'-L_s"- at

MEXICAN INSTITUTE

DIM »INDUSTRIAL PIEDAD which Ls is a link; M is C (O); L_s'is C ^ -Cg (e.g.,) alkylene, in which L_s'independently is optionally substituted with R_T; the R_T Optional is a substituent which is selected from -Cj-Cg alkyl, -Calkenyl₂-C₆, -alky ^ C! -C₆) -OH, -alkyl (CvCgj-O-C ^ Cg alkyl, 3-6 membered heterocycle (e.g., tetrahydrofuranyl), or C carbocyclyl₃-C₆(eg phenyl, cyclohexyl); M 'is -NHC (O) -, -N (Et) C (O) - or -N (Me) C (O) -; and L_s”Is a link. R_D preferably hydrogen, -Cy-Cg alkyl (e.g. methyl), -O-C ^ Cg alkyl (e.g. methoxy, tert-butoxy), methoxymethyl, or -N (C₁-C₆))₂ (for example, -NMe₂).

TR_or can be, without limitation,

<img file="MX346264B_D0176.tif" />

<img file="MX346264B_D0177.tif" />

IMPI wrnvi * Mexican üunwiiiAi INDUSTRIE

<img file="MX346264B_D0178.tif" />

<img file="MX346264B_D0179.tif" />

<img file="MX346264B_D0180.tif" />

<img file="MX346264B_D0181.tif" />

<img file="MX346264B_D0182.tif" />

<img file="MX346264B_D0183.tif" />

in which the stereochemistry at a carbon within the TR group_Dit can be either (R) or (S).

T can also be, without limitation, -L_s-ML_s'- in which L_s is a link; M is C (O); L_s'is Ci-Ce alkylene (for example, in which L_s'independently is optionally substituted with R_T; the R_T Optional is a substituent selected from -C alkyl_rC_6! -alqu¡l (Ci-C₆) -OH, -alkyl (Ci-C₆) -Oalkyl of Ci-Ce, or a carbocyclyl of C₃-C₆ (eg phenyl, cyclohexyl). R_D, is for example -OH; -OC (O) Me; -NHIalkyl ^ -Cg)) (eg -NHMe, -NHEt); -N (alkyl (Ci-C₆)) 2 (for example, -NMe₂, -NEt₂); a 3- to 10-membered heterocyclyl (e.g. pyrrolidinyl,

<img file="MX346264B_D0184.tif" />

IMPI

INSTITUTO MEXICANO 'DE LA PROPERTY INDUSTRIAL imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl) optionally substituted with one or more halogens, oxo; C carbocycle₃-C₁₀ (eg, cyclopentyl) optionally substituted with -OH; -τ-Cg alkyl (eg isopropyl, 3-pentyl) optionally substituted with -OH; or NHR_T in which R_T is a 3- to 6-membered heterocyclyl (eg, thiazolyl, pyrimidinyl). TR_D includes, but is not limited to:

<img file="MX346264B_D0185.tif" />

IMPI

INSTITUTE M HUCA n *

OSLA MtONEDA indwstiual

<img file="MX346264B_D0186.tif" />

<img file="MX346264B_D0187.tif" />

<img file="MX346264B_D0188.tif" />

<img file="MX346264B_D0189.tif" />

<img file="MX346264B_D0190.tif" />

<img file="MX346264B_D0191.tif" />

, in which the stereochemistry at a carbon within the TR group_D it can be either (R) or (S).

For each compound of Formula I, L_K it can also be selected independently each time it appears from a link; -L_s'-N (Rb) C (O) -L_s-; -L_s'-C (O) N (Rb) -L_s-; or CpCe alkylene, C alkenylene₂-C₆, C alkynylene₂-C₆, carbocycle of C₃-C₁₀ or 3- to 10-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, R_T, -OR_s, -S-Rs, -N (R_sRs'). -OC (O) R_S, -C (O) OR_s, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, in which R_T, Rb, Rs, Rs', L_s and L_s'are as defined above.

For Formula I as well as for Formulas l_TO, Ib, Ic, Id, I_and, If, or I_g described below, including each and all the modalities described below, R_to preferably it is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,

<img file="MX346264B_D0192.tif" />

IMPI

ITfSTmnW M1X1CANO

SAY OWNERSHIP

INDUSTRIAL phosphono, thioxo, cyano; or Ci-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cy-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; or -L_TO-OR_S, -La-S-Rs, -La-C (O) R_s, -L_to-OC (O) R_s, -L_to-C (O) OR_s, -L_to-N (R_sR_s'), -L_toS (O) R_s, -L_to-SW₂R_s, -L_to-C (O) N (R_sR_s'), -L_to-N (Rs) C (O) R_s', -L_toN (Rs) C (O) N (R_s'Rs ”)&gt; -L_to-N (R_s)SW₂R_s', -L_to-SW₂N (R_sR_s'), -L_toN (Rs) SO₂N (R_s'R_s”), -L_to-N (R_s) S (O) N (R_s'R_s”), -L_to-OS (O) -R_s, -L_toBEAR)₂-R_s, -La-S (O)₂OR_s, -L_to-S (O) OR_s, -L_to-OC (O) OR_s, -l_toN (Rs) C (O) ORs', -L_to-OC (O) N (R_sR_s'). -L_to-N (R_s) S (O) -R_s', -l_toS (O) N (R_sR_s') or -L_to-C (O) N (R_s) C (O) -R_s', in which L_TO is bond, Cí-Ce alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆.

More preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ct-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted

<img file="MX346264B_D0193.tif" />

IMPI

INSTITUTO MEXICANO Dt LA NOREDAD INDUSTRIAL each time it appears with one or more substituents that are "selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-Ce haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Rather preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C - C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano .

Ls&gt; L_s'and L_s"Preferably they are each independently selected each time they appear from the link; or C ^ Ce alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆A and B can be the same or different. Similarly, L, and L₂, or Y and Z, or YA- and ZB-, or -A-Lí- and -BL₂-, They can be the same or different. In some cases, YAL! - is identical to ZBL₂-, In some other cases, YA-Lí- is different from ZBL₂-.

In one embodiment, A and B are each so

IMPI independent carbocycle or 5-6 membered heterocycle (for

INSTITUTO MKJCANC ORLA MOREDA industrial example, phenyl such as ⁴

L), and are each independently optionally substituted with one or more R_TO. X is 5 to 6 membered carbocycle or heterocycle or 6 to 12 bicyclo

<img file="MX346264B_D0194.tif" />

members (for example, '· o ® —'J, in which X₃is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_TO. Specific examples of X are described earlier in the present application. D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cí-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Οτ-Οβ halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'), and J may also be optionally substituted with one or more R_TO. Of

IMPI rwsTmrro mmqcano

DS THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0195.tif" />

<img file="MX346264B_D0196.tif" />

Rm rn_x , -k. -^Rh^rk T Rn preference, D is O

Rm, in which R_M and Rn are as defined above. Also preferably, D is

J i ^ Lv- or λΑζμ, in which J and Rn are as defined above. M and L₂ are each independently Ci-C bond or alkylene₆, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_l. Preferably, L_1t L₂, and L₃ they are link. Y is -N (R_b) C (O) C (R₁R2) N (R₅) -TR_d, or

-N (R_b) C (O) C (R₃R₄) C (R_sR₇) -TR_d, and Z is -N (R_B) C (O) C (R₈R9) N (R₁₂) -TR_d, or -N (R_b) C (0) C (RioRh) C (Ri₃R₁4) -T-Rd. Ri is Re, and R2 and R5, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0197.tif" />

) which is optionally substituted with one or more R_TO;

R₃ and R₆ 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 (for

<img file="MX346264B_D0198.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY example, \ ^ς ) which is optionally substituted with one or more R_to. Re is R_c, and R₉ and R12, taken together with the atoms to which they are attached, form a 5- to 6 \ __ membered heterocyclic ring (e.g. X) which is optionally substituted with one or more R_TO; and R₁₀ and R₁₃ are each independently R_c, and Rn and Ri₄, 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_TO. T is preferably independently selected each time it appears from -C (O) -Ly'-N (R_b)CABBAGE_s”- or -C (O) -L_Y'-N (R_b) C (O) O-Ls "-. L_Y'is each independently L_s'and preferably each is independently C alkylene_rC₆ (for example, -CH₂- o) and optionally substituted with one or more substituents selected from R_l. T can also be selected, without limitation, from -C (O) -L_AND'-L_S”-, -C (O) -L_AND'-OL_S”-, -C (O) -L_AND'N (R_b) -L_s”-, or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-. In some cases,

<img file="MX346264B_D0199.tif" />

<img file="MX346264B_D0200.tif" />

IMPI

MEXICAN INSTITUTE

DELA INDUSTRIAL PROPERTY minus one of Y and Z is, or both Y and Z are \ 'N-? ?

L_AND’ _orindependent, V —- *, in which the non-limiting examples of R_D include (1) -O-C ^ Ce alkyl, -O-alkenyl of

C₂-C₆, -O-alkynyl of C₂-C₆, Ci-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-6 membered heterocycle; or (2) carbocycle of C₃-C₆ or 3-6 membered heterocycle each independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , thioxo, formyl, cyano, C ^ Ce alkyl, Ο alkenyl₂-Ο₆, C alkynyl₂-C₆, Ci-Ce haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; and the non-limiting examples of L_AND'include C ^ Ce alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ο ^ Οβ-alkyl, -O-C alkenyl₂-C₆, -O-alkynyl of C₂-C₆, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,

<img file="MX346264B_D0201.tif" />

phosphono, thioxo, formyl, cyano, C alkyl_rC₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ct-Cb halogenoalkyl, halogenoalkenyl

IMPI

INSTITUTE MW1CANO

DIMTROPKBAC industrial

C₂-C₆ or halogenoalkynyl of C₂-C₆.

<img file="MX346264B_D0202.tif" />

y is optionally substituted with one or more R_TO; B is &lt;

<img file="MX346264B_D0203.tif" />

<img file="MX346264B_D0204.tif" />

<img file="MX346264B_D0205.tif" />

, and is optionally substituted with one or more R_TO.

Zi is independently selected each time it appears from O, S, NH, or CH₂; and Z₂ is independently selected each time it appears from N or CH. Of

<img file="MX346264B_D0206.tif" />

and A and B are substituted with one or more halogens, such as F or Cl. When A and / or B are benzimidazole substituted with halogen (for example, A is

<img file="MX346264B_D0207.tif" />

modality may have significantly improved pharmacokinetic properties as well as inhibitory activity), the compounds of this improved against certain HCV genotype 1a mutants, compared to the same compounds but with unsubstituted benzimidazole. X is 5- to 6-membered carbocycle or heterocycle or bicyclo

IMPI

IWSIIIUIU MEXICANO DE LA PROPERTY INDUSTRIAL ^ 3, 6 to 12 members (e.g., '--- 1 o, in which X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_TO. Specific examples of X are described earlier in the present application. D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_to, or is substituted with J and optionally substituted with one or more R_to, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C [beta] -C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Preferably D

<img file="MX346264B_D0208.tif" />

<img file="MX346264B_D0209.tif" />

IMPI 'NSTnUTO MEXICANO ML * INDUSTRIAL PROPERTY

<img file="MX346264B_D0210.tif" />

in which R_M and R_N they are how i know

J defined above. Also preferably, D is U ™ jo uXv in which J and R_N they are as defined above. L, and 1-2 are each independently bond or alkylene of Cj-Cg, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. Y is -L_sC (Ri R₂) N (R₅) -T-Rd or -Lg-C (R₃R₄) C (RgR7) -T-Rd, and Z is -L $ C (R₈R₉) N (R₁₂) -TR_d or -Lg-C (R-ioRii) C (R₁₃Ri4) -T-RD. Ri is Rc, and R2 and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0211.tif" />

) which is optionally substituted with one or more R_TO;

R₃ and R₆ are each independently R_c, and R₄ and Rz, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (for example,) which is optionally substituted with one or more R_to. Re is R_c, and R₉ and Ri₂, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example, Λ.) which is optionally substituted with one or more R_TO; and Rio and R13 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 heterocyclic ring (for example,) which is optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -L_Y'-N (R_b)CABBAGE_s”- or -C (O) -L_Y'-N (Rb) C (O) O-Ls "-. L_Y'is each independently L_s'and preferably is independently C ^ -Ce alkylene (e.g. -CH₂-) and optionally substituted with one or more substituents selected from R_L. T can also, without limitation, be selected from -C (O) -L_AND'-L_S”-, -C (O) -L_AND'-OL_S”-, -C (O) -L_AND'N (R_b) -L_s”-, or -C (O) -L_Y'-N (Rb) S (O)₂-L_s”-. In some cases, at least one of Y and Z is, or both Y and Z are so

<img file="MX346264B_D0212.tif" />

<img file="MX346264B_D0213.tif" />

H _- R₀ to go ⁰ or

, in which the examples do not

IMPI

INDUSTRIAL INDUSTRIAL PROPERTY INSTITNVRO MEXICAN independent, limitative of R_D include (1) -O-CpCe alkyl, -O-C-alkenyl₂-C₆, -O-alkynyl of Ο₂-Ο₆, C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-6 membered heterocycle; or (2) carbocycle of C₃-C₆ or 3-6 membered heterocycle each independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; and the non-limiting examples of L_AND'include Ci-Ce alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci-C alkyl₆, -O-alkenyl of C₂-C₆, -Oalkynyl of C₂-C₆, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆,

IMPI in iNSTrnireMsxicANo □ y Dí u PROPERTY industrial C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

In still another embodiment, A and B are each independently 5- to 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such

<img file="MX346264B_D0214.tif" />

as * \ - / '), and are each independently optionally substituted with one or more R_TO. X is 5- or 6-membered carbocycle or heterocycle or 6 to 12-membered bicyclo (for &lt;λΑλ / »« / and v example, \ I or «—'J, in which X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_to. Specific examples of X are described earlier in the present application. D can be, for example, carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 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-C alkyl₆,

<img file="MX346264B_D0215.tif" />

C alkenyl₂-C₆₎ C alkynyl₂-C₆, Ci-C haloalkyl₆,

IMPI

MEXICAN INSTITUTE

DI THE C halogenoalkenyl industrial PROPERTY₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

-N (RsRs'), and J may also be optionally substituted with one or more R_to.

Preferably, D is

<img file="MX346264B_D0216.tif" />

Rm

<img file="MX346264B_D0217.tif" />

in which R_M and Rn are as defined above. Also from

<img file="MX346264B_D0218.tif" />

preference, D is or in which J and R_N they are as defined above. Li and L₂ are each independently Ci-Ce bond or alkylene, and L₃ is bond, Ct-Ce or -C (O) - alkylene, and L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. Y is -GC (R₁R₂) N (R₅) -TR_D or -GC (R₃R₄) C (R₆R₇) -TR_D, and Z is -GC (R₈R₉) N (R₁₂) -TR_D or -GC (Ri₀Rii) C (Ri₃R₁₄) -TR_d. G is independently carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, such as

<img file="MX346264B_D0219.tif" />

or

<img file="MX346264B_D0220.tif" />

independently way is optionally

<img file="MX346264B_D0221.tif" />

substituted with one or more R_TO. Ri is R_c, and R₂ and Rs, taken together with

IMPÍ

IdWlCAN INSTITUTE OF INDUSTRIAL PROPERTY the atoms to which they are attached form a 5 to 6 membered heterocyclic ring (for example,

<img file="MX346264B_D0222.tif" />

is optionally substituted with one or more R_TO; R₃ and Rs are each independently R_c, and R₄ and R₇, taken together with the atoms to which they are attached, form a carbocyclic ring

<img file="MX346264B_D0223.tif" />

which is optionally substituted with one or more R_TO. R₈ is R_c, and R9 and R₁₂, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0224.tif" />

) which is optionally substituted with one or more R_TO; Y

R10 and R13 are each independently R_c, and R11 and Rt₄, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (for example,

<img file="MX346264B_D0225.tif" />

) which is optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -L_AND'-N (R_B) C (O) -Ls ”- or -C (O) AR-nw — m ·,» μ, ·

<img file="MX346264B_D0226.tif" />

Ly'-N (Rb) C (O) OL_s”-. L_Y'is each independently L_s’

IMPI

MELICANO INSTITUTE

OF THE INURRIAL PROPERTY and, preferably, each is independently alkylene of

Ci-C₆ (for example, -CH₂or

<img file="MX346264B_D0227.tif" />

) and optionally substituted with one or more substituents selected from R_L. T can also be selected, without limitation, selected from -C (O) -Ly'-Ls "-, -C (O) -Ly'-O-Ls -C (O) -Ly'-N (Rb )^-Ls ”-, or -C (O)

Ly'-N (Rb) S (O)₂-L_s”-. In some cases, at least one of Y and Z

<img file="MX346264B_D0228.tif" />

non-limiting examples of R_d include (1) -O-Cf-Ce alkyl, -Oalkenyl of C₂-C_6&gt; -O-alkynyl of C₂-C₆, alkyl of Ο,-alquβ, alkenyl of C₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of Ο₃-Ο₆ or 3-6 membered heterocycle; or (2) carbocycle of C₃-C₆ or 3- to 6-membered heterocycle each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,

<img file="MX346264B_D0229.tif" />

IMPI '' njWOMSMCAN

Dt LA FROF1FDAO INDUSTRIAL nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_rC₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; and the non-limiting examples s of L_AND'include C alkylene_rC₆optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Οί-Cb alkyl, -O-C alkenyl₂-C₆, -O-alkynyl of C₂-C₆₎ or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , thioxo, formyl, cyano, C- | -C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

In yet another embodiment, A and B are each independently 5- to 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as

<img file="MX346264B_D0230.tif" />

), and are each independently optionally substituted with one or more R_TO. X is 5-membered carbocycle or heterocycle or 6 to 12-membered bicyclo (for example,

<img file="MX346264B_D0231.tif" />

a, in which X₃ is N and is directly linked

-L₃-D) and is optionally substituted with one or more R_to. Specific examples of X were described

<img file="MX346264B_D0232.tif" />

earlier in the present application. D can be, for example, carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_to. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ -Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C, -C halogenoalkyl_6lC halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (RsRs'). YJ can also be optionally substituted with one

<img file="MX346264B_D0233.tif" />

which R_M and Rn are as defined above. Also from

<img file="MX346264B_D0234.tif" />

as defined above.

L! and L₂ they are each one way

<img file="MX346264B_D0235.tif" />

Ci-C bond or alkylene independent₆, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably Li, L₂, and L₃ they are link. Y is -N (R_B) C (O) C (R₁R₂) N (R₅) -TRd or -N (R_b) C (O) C (R₃R₄) C (R₆R₇) -TR_d, and Z is -GC (R₈R₉) N (R₁₂) -TR_Dor -GC (R₁₀Rn) C (R₁₃Ri₄) -TR_D; or Y is -G-CíR, R₂) N (R₅) -TR_D or -GC (R₃R₄) C (R₆R₇) -TR_D, and Z is -N (R_B) C (O) C (R₈R₉) N (R₁₂) -TR_D or -N (R_b) C (O) C (R₁₀Rh) C (Ri₃Ri₄) -T-Rd. Ri is Re. And R2 and R5, 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_TO; R3 and R_B 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 (for example,) which is optionally substituted with one or more R_TO.

R₈ is R_c, and Rg and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0236.tif" />

which is optionally substituted with one or more R_to; and R₁₀ and R13 are each independently R_c, and

Rn and Rm, taken together with the atoms to which they are

<img file="MX346264B_D0237.tif" />

together, they form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., X) which is optionally substituted with one or more R_TO- G is independently carbocycle of Ο₅-Ο_δ or 5- to 6-membered heterocycle, as independently optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -L_AND'N (R_b)CABBAGE_s”- or -C (O) -L_Y'-N (R_b) C (O) OL_s”-. L_Y'is each independently L_s'and, preferably, each is independently C ^ Ce alkylene (e.g. -CH₂- o) and optionally substituted with one or more substituents selected from R_L. T can also, without limitation, be selected from -C (O) -L_AND'-L_S”-, -C (O) -L_AND'-OL_S”-, -C (O) -L_AND'N (R_b) -L_s”-, or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-. In some cases, Y is / fí^Land O as described above, and Z is

<img file="MX346264B_D0238.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0239.tif" />

In some other cases, Y is described above.

<img file="MX346264B_D0240.tif" />

<img file="MX346264B_D0241.tif" />

how I know

<img file="MX346264B_D0242.tif" />

as described above.

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

<img file="MX346264B_D0243.tif" />

), and B is

<img file="MX346264B_D0244.tif" />

IMPI

O), and B is carbocycle or heterocycle of 5 to 6 rmvro Mexican DI LA INDUSTRIAL PROPERTY members (eg, phenyl such as * \ = /). A and B are each independently optionally substituted with one or more R_TO. Z, is independently selected each time it appears from O, S, NH, or CH₂; and Z₂ it is independently selected each time it appears from N or OH. X is 5 to 6 membered carbocycle or heterocycle or 6 to 12 bicyclo

<img file="MX346264B_D0245.tif" />

members (for example, '--- / o ®, in which X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_TO. Specific examples of X are described earlier in the present application. D is carbocycle of Ο₅-Ο₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆₁ 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,

<img file="MX346264B_D0246.tif" />

IMPI

INSTITUTO M EXICANO »E LA MtOHBDAD ÍSnUSTRIAL phosphono, thioxo, formyl, cyano, C- | -C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C &lt;-C haloalkyl_g, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Of

<img file="MX346264B_D0247.tif" />

^rm

<img file="MX346264B_D0248.tif" />

, in which R_M and R_N they are as defined above. Also preferably, D is

<img file="MX346264B_D0249.tif" />

<img file="MX346264B_D0250.tif" />

in which J and R_N they are as defined above. Li and L₂ are each independently Ci-C bond or alkylene₆, and L₃ is bond, C ^ Ce alkylene or -C (O) -, and L ,, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. When A is 5- to 6-membered carbocycle or heterocycle (for example, phenyl such as

<img file="MX346264B_D0251.tif" />

), Y is -N (R_b) C (O) C (R₁R₂) N (R₅) -TR_d, -N (R_b) C (O) C (R₃R₄) C (R₆R₇) -TR_d, -GC (R₁R₂) N (R₅) -TR_d or -GC (R₃R₄) C (R₆R₇) -TR_d, and Z is -L_s-C (R₃Rg) N (R1 ₂) -T-Rd or “Ls^_C (R-iqRii) C (Ri₃Ri₄)^-T-Rd. When B is 5- to 6-membered carbocycle or heterocycle (e.g., phenyl such

<img file="MX346264B_D0252.tif" />

IMPI

INSTTTVTp MEXICAN

DI MIMPIMAD «• USTMM —fi as⁵ \=/ ^ξ ). Y is -LS-C (R1R2) N (R5) -T-RD or -LS-C (R3R4) C (R6R7) T-Rd, and Z is -N (RB) C (O) C (R8R9) N (R12) -T-RD, -NÍRbMOJC ^ oRh) C (Ri3Ri4) -T-Rd, -GC (R8R9) N (R12) -T-Rd or -GC (RioRii) C (Ri3Ri4)^-TRd. Ry is R_c, and R2 and Rs, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example, X ^ς) which is optionally substituted with one or more R_TO; R₃ and R₆ 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 (for example,) which is optionally substituted with one or more R_to. Re is R_c, and R₉ and Ry₂, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0253.tif" />

which is optionally substituted with one or more R_TO; and R10 and R13 are each independently R_c, and R11 and R14, taken together with the atoms to which they are attached, form a carbocyclic ring or

<img file="MX346264B_D0254.tif" />

<img file="MX346264B_D0255.tif" />

IMPI

INSTITUTO MBT1CANO Oí LA PROPERTY INDUSTRIAL 5-6 membered heterocyclic (for example, which is optionally substituted with one or more R_TOG is independently carbocycle of C₅-C₆ or 5- to 6-membered heterocycle,

Η H such as * —non— 'and independently is optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -L_Y'-N (Rb) C (O) -L_s”- or -C (O) -L_Y'-N (Rb) C (O) OL_s”-. L_Y'is each independently L_s'and preferably each is independently C-C alkylene₆ (for example, -CH₂- or

<img file="MX346264B_D0256.tif" />

) and optionally substituted with one or more substituents selected from R_l. T can also, without limitation, be selected from -C (O) -L_AND'-Ls ”-, -C (O) -Ly'-OL_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 when A is a 5- to 6-membered carbocycle or heterocycle (e.g., phenyl such

<img file="MX346264B_D0257.tif" />

<img file="MX346264B_D0258.tif" />

IMPI

MEXICAN INSTITUTE

K DEATH

INDUSTRIAL

<img file="MX346264B_D0259.tif" />

as described above, and Z is

<img file="MX346264B_D0260.tif" />

as described above.

In some other cases when B is 5- to 6-membered carbocycle or heterocycle (e.g., phenyl such as

<img file="MX346264B_D0261.tif" />

<img file="MX346264B_D0262.tif" />

<img file="MX346264B_D0263.tif" />

as described above, and Z is

<img file="MX346264B_D0264.tif" />

described above.

The present invention also includes compounds of Formulas I, l_TO, Ib. Ic and Id as described in the present application (including each embodiment described thereunder) and pharmaceutically acceptable salts thereof, in which:

D is carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_TO; or D is

<img file="MX346264B_D0265.tif" />

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R_TO, in which J is C3-C15 carbocycle or 3- to 15-membered heterocycle (for example, a 3- to 6-membered monocycle, a fused 6 to 12-membered bicycle, bridged or spiro structure, a 10-membered tricycle to 15 membered containing fused rings, bridged or spiro structure, or a 13 to 15 membered carbocycle or heterocycle) and is optionally substituted with one or more R_TO, or J is -SF₅; or D is hydrogen or R_TO;

R_to is independently selected each time it occurs from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Lb-Re, in which two R_TO Adjacent, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, may optionally form carbocycle or heterocycle;

* Lb is selected independently each time it appears from L_s; or CiC-io alkylene, C alkenylene₂-C₁₀ or C alkynylene₂-C₁₀, each of which optionally has 1, 2, 3, 4, or 5 carbon atoms independently replaced with O, S, or N (R_B), and each of said Ci-C alkylene₁₀, C alkenylene₂-C₁₀ or C alkynylene₂-C₁₀ independently is optionally substituted with one or more R_L;

Re is selected independently each time it appears from -OR_s, -MR_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’,

IMPI

MfltlCANO INSTITUTE

OF THE MOUEOAB

INDUSTRIAL

<img file="MX346264B_D0266.tif" />

-N (R_s) C (O) N (Rs'Rs ”), -N (R_s)SW₂Rs', -SO₂N (R_sR_s’),

-N (Rs) SO₂N (R_s'R_s”), -N (R_s) S (O) N (Rs'R_s”), -OS (O) -R_s, -BEAR)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 (R_sR_s'), -N (Rs) S (O) -R_s', -S (O) N (R_sRs'), -P (O) (OR_S)₂, = C (R_sRs'), or -C (O) N (R_s) C (O) -Rs'; or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle; or carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle (e.g., 7 to 12-membered carbocycle or heterocycle), each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy , mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Cí-alkyl, C-alkenyl₂-C₆, C alkynyl₂-C₆, geno, -Οβ haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -OR_s, -S-Rs, -C (O) R_S, -C (O) OR_S, or -N (R_sRs')

R_L is independently selected each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -OR_s, -S-Rs, -C (O) R_S, -OC (O) Rs, -C (O) ORs, -N (R_SR_S'), -S (O) R_s, -SO₂R_s, -C (O) N (R_sRs') or -N (R_S) C (O) R_S'; or carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle (e.g., carbocycle of

C₃-C₆ or 3-6 membered heterocycle), each of which

<img file="MX346264B_D0267.tif" />

independently is optionally substituted each occurrence with one or more substituents selected from

IMPI

MU1CANO INSTITUTE

FROM INDUSTRIAL PROPERTY halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C - C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; in which two R_L Adjacent, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, may optionally form carbocycle or heterocycle.

In one embodiment, A and B are each independently 5- to 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 R_TO (Preferably, A and B are each independently substituted with at least one halogen such as F). X is 5- to 6-membered carbocycle or heterocycle or 6 to 12-membered bicyclo (preferably X is \ --- ', where X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_TO. D is a carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is substituted with J and optionally substituted with one or more R_TO. J is carbocycle of C₃-C₆, 3 to 6 membered heterocycle, 6 to 12 bicycles

<img file="MX346264B_D0268.tif" />

IMPI

INSTITUTO MEXICANO DE LA HtOPUDA »members, 10 to 15 membered tricycle, or 13 to 15 membered carbocycle / heterocycle, and J is optionally substituted with one or more R_TO, Preferably, J is substituted with a carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CtC alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_SR_S'), or (2) trimethylsilyl, -OR_s, -MR_s, -C (O) R_S; and J can also be optionally j

substituted with one or more R_TO. Preferably, D is or

J, in which J is as defined above, and each R_Nis independently selected from R_D and is preferably hydrogen or halogen such as F. Li and L₂ are each independently Cí-Ce bond or alkylene, and L₃ is bond, C ^ Ce alkylene or -C (O) -, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_L.

IMPI

INSTITUTO MBUCANO DE U HtOPIRDAD INDUSTRIAL

Preferably, L₂, and L₃ are pnlarp and

-N (R_b) C (O) C (R₁R₂) N (R₅) -TR_d, -N (R_b) C (O) C (R₃R₄) C (R₆R₇) -TR_d, -GC (R₁R₂) N (R₅) -TR_d or -GC (R₃R₄) C (R₆R₇) -TR_d. Z is -N (R_b) C (O) C (R₈R₉) N (R₁₂) -TR_d, -N (R_b) C (0) C (RioRh) C (Ri₃Ri₄) -TR_d, -GC (R₈Rg) N (Ri₂) -TR_D or -GC (R-ioRii) C (Ri₃Ri₄) -T-Rd- Ri is Re! and R2 and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,) or 6 to 12-membered bicycles (for example which is optionally substituted with one or more R_TO; 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 (for example,) or 6 to 12-membered bicyclo which is optionally substituted with one or more R_to. R₈ is R_c; and R₉ and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,) or impi bicyclo mUican iNSTrtvro

OF RARE

INDUSTRIAL

<img file="MX346264B_D0269.tif" />

to 12 members (eg, \) which is optionally substituted with one or more R_TO; and R₁₀ and R₁₃ are each independently R_c, and Rn and Ri₄, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring

<img file="MX346264B_D0270.tif" />

or 12-membered bicycle which is optionally substituted with one or more

R_to. G is independently carbocycle of C₅-C₆ or 5-membered heterocycle, such as and independently optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -Ly'-N (Rb) C (O) -L_s”- or -C (O) -L_AND'N (R_b) C (O) OL_s”-. L_Y'is each independently L_s'and, preferably, each is independently C ^ Cg alkylene (e.g. -CH₂-

<img file="MX346264B_D0271.tif" />

) and optionally substituted with one or more substituents selected from R_L. T can also, without limitation, be selected from -C (O) -Ly'-L_s”-, -C (O) IMPI itmiiu your Mexican

Dt name it

INDUSTRIAL

<img file="MX346264B_D0272.tif" />

Ly'-O-Ls ”-, -C (O) -Ly'-N (Rb) -Ls” -, or -C (O) -L_Y'-N (Rb) S (O)₂-L_s”-. In

<img file="MX346264B_D0273.tif" />

<img file="MX346264B_D0274.tif" />

<img file="MX346264B_D0275.tif" />

<img file="MX346264B_D0276.tif" />

y is optionally substituted with one or more R_TO; B is

<img file="MX346264B_D0277.tif" />

NH substituted with one or more R_TO.

and is optionally

Z₁ is selected so

<img file="MX346264B_D0278.tif" />

independent each time it appears from O, S, NH or CH₂; and Z₂

IMPI

INSTITUTE ΜΜΚΆΝΟ

FROM ΙΛ INDUSTRIAL PROPERTY is selected independently each time it appears from N or CH. Preferably A and B are each independently substituted with at least one halogen such as F.

Also preferably, A is

<img file="MX346264B_D0279.tif" />

and A and B are substituted with one or more halogens, such as F or CL When A and / or B are benzimidazole substituted with halogen (for

<img file="MX346264B_D0280.tif" />

of this embodiment may have significantly improved pharmacokinetic properties as well as enhanced inhibitory activity against certain HCV genotype 1a mutants, compared to the same compounds but with unsubstituted benzimidazole. X is 5- to 6-membered carbocycle or heterocycle or jvv \ t Mm \ / 6 to 12-membered bicyclo (preferably X is v — i, where X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_TO. D is a carbocycle of C₅-C_and or 5- to 6-membered heterocycle (e.g. phenyl), and is substituted with J and optionally substituted with one or more R_TO. J is carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo,

IMPI fNmjurumexicano

W THE PROPERTY

INDUSTRIAL ^ * 5 = 5 ^^ 10-15 membered tricycle or r.arhnr.icln / 13-15 membered heterncycle, and J is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CpCs, alkenyl of C₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_sRs')&gt; or (2) trimethylsilyl, -O-Rs, -SR_s, or -C (O) R_S; and J can also be optionally j

Rn ^^^^ A ^^^ Rn replaced with one or more R_TO. Preferably, D is A, or

J, in which J is as defined above, and each R_n is independently selected from R_D and is preferably hydrogen or halogen such as F. L, and L₂ are each independently bond or alkylene of C ^ Ce, and L₃ is bond, C ^ Ce alkylene or -C (O) -, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_LIMPI

INSTITUTO MEXICAN ·

OtLAMOHtOA »

INDUSTRIAL

<img file="MX346264B_D0281.tif" />

Preferably, L_1t L₂, and L₃ they are link.

Y is -L_s-C (R₁R₂) N (R₅) -TR_d or

-Ls-C (R₃R4) C (R6R7) -T-Rd- z

C (RioRi i) C (Ri3Ri4) -T-RdRi is atoms to which these are -Ls-C (R₈R9) N (R₁₂) -T-Rd or -Ls^-

Rc; and R2 and Rs, taken together with the are joined, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0282.tif" />

or bike

I \ to 12 members (e.g. X) which is optionally substituted with one or more R_TO; 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 (for example,

<img file="MX346264B_D0283.tif" />

or 12-membered bicycle which is optionally substituted with one or more

R_to. Re is R_c; and Rg and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0284.tif" />

) or 6 to 12 membered bike (for example,

<img file="MX346264B_D0285.tif" />

<img file="MX346264B_D0286.tif" />

IMPI

INSTITUTO MEXICANO DE LA WliDAO INDUSTRIAL) which is optionally substituted with one or more R_TO; Y

Rio and R13 are each independently R_c, and Rn and Ri₄, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (for example, \) or 6 to 12-membered bicyclic ring which is optionally substituted with one or more R_TO. T is preferably independently selected each time it appears from -C (O) -Ly'-N (R_b)CABBAGE_s”- or -C (O) -L_Y'-N (Rb) C (O) OL_s”-. Ly 'is each independently L_s'and preferably each is independently C! -C alkylene₆ (for example, -CH₂- or

<img file="MX346264B_D0287.tif" />

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

<img file="MX346264B_D0288.tif" />

or

<img file="MX346264B_D0289.tif" />

<img file="MX346264B_D0290.tif" />

in which non-limiting examples of R_D include (1) -O-Ci-Cealkyl, -O-Ci-alkenyl₂-C₆, -O-alkynyl of C₂-C₆, CfCe alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-6 membered heterocycle; or (2) carbocycle of C₃-C₆ or 3-6 membered heterocycle each independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , thioxo, formyl, cyano, C ^ Cs alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; and the non-limiting examples of L_AND'include Ci-C alkylene₆ optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci-C alkyl₆, -Oalkenyl of C₂-C₆, -O-alkynyl of C₂-C₆, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl,

IMPI ”gg« iisa »» WUSTItlAL

<img file="MX346264B_D0291.tif" />

C alkenyl₂-C₆, C alkynyl₂-C₆, C &lt;-C haloalkyl_6lC halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

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

D

<img file="MX346264B_D0292.tif" />

in which:

R_nb each is independently selected from R_B;

R_c'each is independently selected from R_c;

R_D'each is independently selected from R_D;

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_TO;

R₉ and R₁₂, 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_TO;

<img file="MX346264B_D0293.tif" />

IMPI ttCTmrronixKMtt) of the ntopiEtua

<img file="MX346264B_D0294.tif" />

A, B, D, X, Lt, L_2i L_3i T, R_to, Rb. Rc, and Rd are as previously described in Formula I.

In this regard, A and B are preferably independently selected from carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more R_TO. More preferably, at least one of A and B is phenyl (eg,), and is optionally substituted with one or more R_TO. Quite preferably, both A and B are each &amp; / \ independently phenyl (eg, * \ = / '), and are each independently optionally substituted with one or more R_TO.

Preferably D is selected from carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 8 to 12 membered bicycles, and is optionally substituted with one or more R_TO. Preferably D can also be selected from C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, and is optionally substituted with one or more R_L. More preferably, D is carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is substituted with one or more R_M, in which 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_TO. More preferably, D is phenyl, and is substituted with one or more R_M, in which R_M it is as defined above. By way of

<img file="MX346264B_D0295.tif" />

IMPI IRSTHUroMIXICMO DIUHIOnEtMD INDUSTRIAL

<img file="MX346264B_D0296.tif" />

R &lt;T ^rn rather preferred, D is ojw or λ / w, in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_n they can also be preferably halogen such as F.

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

Rather preferably, D is

<img file="MX346264B_D0297.tif" />

<img file="MX346264B_D0298.tif" />

<img file="MX346264B_D0299.tif" />

in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they may also preferably be halogen such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, and is optionally substituted with one or more R_TO. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, or

<img file="MX346264B_D0300.tif" />

benzo [d] [1,3] dioxol-5-yl, and is substituted with one or more R / De

<img file="MX346264B_D0301.tif" />

IMPI n '⁵™^m ** χάνο

Dt THE INDUSTRIAL PROPERTY rather preferred way, D is

<img file="MX346264B_D0302.tif" />

<img file="MX346264B_D0303.tif" />

/ '\ Γ O

Jw, or JL, and is optionally substituted with one or more Rm

Preferably R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C - C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, haloalkyl, -Cg, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Cf-Cg alkyl,

<img file="MX346264B_D0304.tif" />

C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, or carboxy. Rather preferably, R_M is C ^ Ce alkyl 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, phosphono, thioxo, or "cyano; or R_M is -L_S-R_AND, in which L_s is a bond or alkylene of CpC ', and R_and is -N (R_SR_S'), -OR_s, -C (O) R_S, -C (O) OR_S, -C (O) N (R_sRs'), -N (R_s) C (O) Rs ', -N (Rs) C (O) ORs', -N (R_s)SW₂R_s', -SO₂R_s, -MR_s, or -P (O) (OR_S)₂, in which R_s and Rs' can, for example, each be independently selected each occurrence from (1) hydrogen or (2) C ^ Ce alkyl optionally substituted each occurrence with one or more halogens, hydroxy, -O -Ci-Ce alkyl or 3-6 membered heterocycle; or R_M is Ci-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally substituted each time it appears with one or more substituents listed below.

<img file="MX346264B_D0305.tif" />

IMPI * fWTnVTO MMKARO

D »LA MOREDA ·

INDUSTRIAL.

100 selected from halogen, hydroxy, mercapto aminn oarhnxy nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C alkyl_;-C₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, halogenoalkynyl of₂-Ο₆, -C (O) OR_S, or -N (RsRs'). More preferably, R_M is halogen (e.g. fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or 0-alkyl_Γ0₆ (e.g., methyl, isopropyl, tert-butyl), C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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_S-R_AND in which L_s is a link and R_ANDis -N (R_SR_S'), -OR_s, -N (Rs) C (O) ORs', -N (Rs) SO₂Rs', -SO₂Rs, or -SRs For example in cases where L_s is a link, R_AND en -NíalquiKCiC₆)) 2 (for example, -NMe₂); -N (alkylene (C₁-C₆) -O-C! -C alkyl₆)₂(for example -N (CH₂CH₂OMe)₂); -hKalquil ^ -CeXalkyleneíCvCehOalkyl of C ^ Ce) (for example -N (CH₃) (CH₂CH₂OMe)); -O-C ^ Cs alkyl (eg -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-halogenoalkyl of 0, -Ce (for example, -OCF₃, -OCH₂CF₃); -O-alkylene-C ^ Cej-piperidine (for example, -O-CH₂CH₂-1-piperidyl); -N (alkyl (C₁-C₆) C (O) O-CpCe alkyl (e.g., -N (CH₃) C (O) OCH₂CH (CH₃)₂), -N (alkyl (Ci-C₆)SW₂-alkyl of C ^ Ce (for example, -N (CH₃)SW₂CH₃); -SW₂Cy-Ce alkyl (e.g. -SO₂I); -SW₂-Ci-C halogenoalkyl₆ (for example, -SO₂CF₃); or

IMPI

INSTITUTO MEXICANO ocunmiM ·

-S-halogenoalkyl of Ο, -Οθ (e.g. SCF₃) Also preferably R_M is -L_s-Re in which L_s is alkylene of Οι-Ο₆ (for example, -CH₂-, -C (CH₃)₂-, -C (CH₃)₂-CH₂-) and R_AND is -OR_s, -C (O) OR_S, -N (R_S) C (O) OR_S', or -P (O) (ORs)₂. For example R_M is -βΙςυίΙβηίΟ, -Οβ) OR_s (for example, -C (CH₃)₂-CH₂-OMe); -alqu¡len (Ci-C₆) -C (O) ORs (for example, -C (CH₃)₂-C (O) OMe); -alkylene (C - C₆) -N (R_S) C (O) OR_S'(for example, -C (CH₃)₂-CH₂-NHC (O) OCH₃); or -alkylene ^ -Ce) P (O) (OR_s)₂ (for example, -CH₂-P (O) (OEt)₂). Also more preferably R_M is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CpCe alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Cf-Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (R_sRs') ^By example R_m is cycloalkyl (for example, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1 -yl, cyclohexyl), phenyl, heterocyclyl (for example, morpholin-4-yl, 1,1-dioxidothomorpholin-4- yl, 4-methylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, pyrolidin-1-yl, piperidin-1-yl, 4-methylpiperidin-1-yl, 3,5-d¡meth¡lp¡ peridin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6 (dimethylamine) pyridin-3-yl). Rather preferably, R_M is 0.06 alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g. tert-butyl,

<img file="MX346264B_D0306.tif" />

IMPI

102 INDUSnUAt

CF₃). ' ” ......

More preferably, D is carbocycle of C₅-C₆, 5- to 6-membered heterocycle or 6 to 12-membered bicyclo and is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, in which said carbocycle of C₃-C_s or 3-6 membered heterocycle independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CrCe, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C_S) C (O) OR_S or -N (RsRs'), and J may also be optionally substituted with one or more R_TO. Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably, J is at least substituted with one carbocycle of C₃-C₆ or 3-6 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, Cí-Ce alkyl, C alkenyl₂-C₆, alkynyl

<img file="MX346264B_D0307.tif" />

103

IMPI

INSTITUTO MEXICANO ORLA MOHEDA »INDUSTRIAL

C₂-C₆, Ci-Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs') Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is 6 to 12 membered bicycles (for example, a fused 7 to 12 membered bicycles, bridged or spiro structure comprising a nitrogen ring atom through which J is covalently bonded to D) and is optionally substituted with one or more R_to- More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C alkyl_rC₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_rC₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C_and, C (O) OR_S or

J

<img file="MX346264B_D0308.tif" />

-N (RsRs'). Quite preferably, D is ΛΛΛΓ, in which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆,

<img file="MX346264B_D0309.tif" />

104

IMPI «ΤΓΤνΤΟ MEXICAN

M UMPtONITY wousntiAi 3 to 6 membered heterocycle or 6 to 12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CpCe alkyl, C alkenyl₂-Ce, C alkynyl₂-C₆, C ^ -Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'). Also from

J RtK χ-L /^RnII Rm Γ Rn preference, D is «ΛΛΛΓ, in which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is substituted with a carbocycle of C₃-C₆ or 3-6 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, Cí-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, halogenoalkenyl

C₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'), and J may also be optionally substituted with one or more R_TO. Also from

IMPI «ΤΓΓνΤΟ MEXICAN • ílAB PIEDAD

INDUSTRIAL

<img file="MX346264B_D0310.tif" />

105

<img file="MX346264B_D0311.tif" />

preferably, D is, and J is carbocycle of C₃-C₆ or 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CtCb alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, halogenoalkyl of Ο ^ Οβ, halogenoalkenyl of C₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs')

X is preferably carbocycle of C₅-C₆, 5- to 6-membered heterocycle, or 6 to 12-membered bicycles (for example,

<img file="MX346264B_D0312.tif" />

ov — y, in which X₃ is N and is directly linked to -L₃D), and is optionally substituted with one or more R_TO or R_F. Non-limiting examples of X are described earlier in the present application.

L-ι and L₂ preferably they are independently Ci-Ce bond or alkylene, L₃ preferably selected from

IMPI «ST1TWTO MEXICAN

D £ LA PWOHSnAD

WDUJTIUAI

<img file="MX346264B_D0313.tif" />

106 bond, C ^ Ce or -C (O) - alkylene, and L₂, and L₃ are each independently optionally substituted with one or more R_l. More preferably, Li, L₂ and L₃ are each independently bond or alkylene of CrC₆ (for example, -CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Rather preferably, L ,, L₂ and L₃ they are link.

R₂ and Rs, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6 to 12-membered bicycles (for example,

<img file="MX346264B_D0314.tif" />

which is optionally substituted with one or more R_TO.

Rg 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 bicyclo (for example,

<img file="MX346264B_D0315.tif" />

<img file="MX346264B_D0316.tif" />

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

-TR_D'can, without limitation, be independently selected each time it appears from -C (O) -L_AND'-, -C (O) OLy'-Rd', -C (O) -Ly'-N (R_b)CABBAGE_s”-Rd ', -C (O) -L_Y'-N (R_b) C (O) OL_s”-R_d',

IMPI

INDUÍTMAl,

<img file="MX346264B_D0317.tif" />

107

-N (Rb) C (O) -L_Y'-N (R_b)CABBAGE_s”-R_d', -N (R_b)CABBAGE_Y'-N (R_b) C (O) OL_s”R_d', or -N (R_b)CABBAGE_Y'-N (R_b) -L_s”-Rd ', in which L_AND'is each independently L_s'and preferably each is independently alkylene of Ο, -Οβ (e.g., -CH₂- o) and is optionally substituted with one or more substituents selected from R_L. Preferably -TR_D'is selected independently each time it appears from -C (O) -L_AND'-M'L_s”-Rd 'or -N (R_b)CABBAGE_Y'-M'-L_s”-Rd 'More preferably, -TR_d'is selected independently each time it appears from -C (O) -L_Y'-N (R_b)CABBAGE_s”-R_d'or -C (O) -L_Y'-N (R_b) C (O) OL_s”R_d'. Rather preferably, -TR_D'is selected independently each time it appears from -C (O) -L_AND'-N (R_B) C (O) Rd 'or -C (O) -L_Y'-N (R_b) C (O) OR_d', in which L_AND'preferably each is independently Ci-C alkylene₆ (for example,

-CH₂- or

<img file="MX346264B_D0318.tif" />

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

Rnb and Rc 'are preferably hydrogen, and R_D'preferably is selected independently each time it appears from R_AND. More preferably, R_D'is independently selected each occurrence from Ci-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each one of those

<img file="MX346264B_D0319.tif" />

LMPI. _ MEXICAN INSTnyiO

108 díuiuohioad

INDUSTMAL 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, carbocycle of C₃-C₆ or 3-6 membered heterocycle; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

R_to preferably it is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₈ or halogenoalkynyl of C₂-C₆; or -L_TO-OR_S, -L_TO-MR_s, -L_TO-C (O) R_S, -L_TO-

<img file="MX346264B_D0320.tif" />

IMPI

INSTITUI * MEXICAN no DEUnonEDAD ^{one υ} INDUSTRIAL

OC (O) R_S, -L_to-C (O) OR_S1 -L_to-N (R_sRs'), -L_to-S (O) R_s, -La-SO₂R_s, -L_toC (O) N (R_SR_S'), -L_to-N (Rs) C (O) Rs', -L_to-N (Rs) C (O) N (R_s'R_s”), -L_toN (Rs) SO₂R_s', -L_to-SW₂N (R_sR_s'), -L_to-N (Rs) SO₂N (R_s'R_s”), -L_toN (Rs) S (O) N (R_s'Rs ”), -La-OS (O) -R_s, -La-OS (O)₂-R_s, -L_to-SW)₂OR_s,

-L_to-S (O) OR_s, -La-OC (O) OR_s, -L_to-N (Rs) C (O) ORs', -L_to-OC (O) N (R_sR_s'), -L_to-N (Rs) S (O) -Rs', -L_to-S (O) N (R_sRs') or -L_to-C (O) N (R_s) C (O) -Rs'. in which L_TO is bond, Ci-C alkylene₆, C alkenylene₂-C₆ or C alkynylene₂-C₆.

More preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C &lt;-C alkyl_5: C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CpCe alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C.-C halogenoalkyl₆. C halogenoalkenyl₂-C₆ or halogenoalkinyl of C₂-C₆.

Rather preferably, R_to is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano;

or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each

IMPI

INSTnUT · MEXICAN

M THE NOMEDA »

INDUrnUAL

<img file="MX346264B_D0321.tif" />

110 of which independently it is optionally substituted 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 they are each independently selected each time they appear from the link; or alkylene of 0_Γ0₆, C alkenylene₂-C₆ or C alkynylene₂-C₆.

A and B can be the same or different. Similarly, Li and L₂ They 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_TO; D is phenyl, and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_to. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 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-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, CyCe haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

-N (R_sRs'). and J can also be optionally substituted with one

<img file="MX346264B_D0322.tif" />

111

IMPI “tNSTTfth» MEXICAN

MlZntQMBA »INDfSWLAL

<img file="MX346264B_D0323.tif" />

Rm and Rn are as defined above. Also from

<img file="MX346264B_D0324.tif" />

<img file="MX346264B_D0325.tif" />

, in which J and R_N they are as defined above. M and L₂ are each independently bond or alkylene of C ^ Cg, and L₃ is bond, Cj-Cg or -C (O) - alkylene, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'-N (R_B)CABBAGE_s”-Rd 'or -C (O) -L_Y'-N (R_b) C (O) OL_s”-R_d', in which L_AND'is Ci-C alkylene₆ (for example, -CH₂-) and is optionally substituted with one or more substituents selected from Rl, and L_s"Preferably link. -TR_D'may also, without limitation, be selected from -C (O) -L_AND'-L_S”-R_D', -C (O) -L_AND'-OL_S”-R_D', -C (O) -L_Y'-N (Rb) -L_s”-R_d', or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-Rd '. Preferably R₂ and R₅, taken together with the atoms to which they are attached, form

<img file="MX346264B_D0326.tif" />

which is optionally substituted

<img file="MX346264B_D0327.tif" />

112 with one or more R_TO; R9 and R12, taken together with the atoms to which

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPERTY which these are united, form which is optionally substituted with one or more R_TO.

In another embodiment of this aspect, A and B are each ΛΆ — i independently phenyl (for example, \ = / ^?), and are each independently optionally substituted with one or more R_TO (Preferably, A and B are each independently substituted with at least one halogen such as F).

X is '---', in which X₃ is N and is directly linked to -L₃D, and X is optionally substituted with one or more R_TO or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_to. J is carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, 10-15 membered tricycle or 13-15 membered carbocycle / heterocycle, and J is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C_B&gt; 3-6 membered heterocycle, 6-12 membered bicycles, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto , amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo,

IMPI instttut · muucano

Oí ΙΛ INDUSTRIAL PROPERTY

<img file="MX346264B_D0328.tif" />

113 formyl, cyano, C alkyl_rC_6i C2-C alkenyl₆, alkynyl

C₂-C₆, Ci-Ce haloalkyl, 0 haloalkenyl₂-0₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_sRs')&gt; or (2) trimethylsilyl,

-OR_s, -MR_s or -C (O) R_S; and J can also be optionally

J replaced with one or more R_TO. Preferably, D is U or J, where J is as defined above, and each R_Nis independently selected from R_D and is preferably hydrogen or halogen such as F. I-! and L₂ are each independently bond or alkylene of C ^ Ce, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and L1, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'N (R_b)CABBAGE_s”-Rd 'or -C (O) -L_Y^,-N (Rb) C (O) O-Ls ”-Rd^,&gt; in which L_AND'is Ci-C alkylene₆ (for example, -CH₂-) and optionally is substituted with one or more substituents selected from Rl, and Ls "is preferably bond. -TR_D'may also, without limitation, be selected from -C (O) -L_Y'-Ls ”-Rd', -C (O) -L_Y'-O25

Ls "-Rd '. -C (O) -Ly'-N (Rb) -Ls ”-Rd ', or -C (O) -Ly'-N (R_b) S (O) 2-Ls "-Rd '. R2

<img file="MX346264B_D0329.tif" />

114 and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

IMPI ιι * ιπυιυ mMcan · '

DE M MONEDA »industrial

<img file="MX346264B_D0330.tif" />

\ ic) or 6 to 12 membered bicyclo (e.g. \) which is optionally substituted with one or more R_TO; and R₉ and R₁₂, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0331.tif" />

<img file="MX346264B_D0332.tif" />

which is optionally substituted with one or more R_TO.

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

R5

To go₂

N

R_d'-T r₉ T '^{2 1}

T Ro '

<img file="MX346264B_D0333.tif" />

Rc '

Rc '

Ib in which:

R_c'each is independently selected from R_c;

<img file="MX346264B_D0334.tif" />

IMPI! «TTrUT» M15 «CANO

OF THE PROPERTY

INDUSTRIAL

115

R_d'each is independently selected from R_D;

R₂ and Rs&gt; 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_to;

R₉ and R₁₂, 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_TO;

A, B, D, X, Li, L₂, L₃, T, R_to, R_c, and Rd are as previously described in Formula I.

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

<img file="MX346264B_D0335.tif" />

<img file="MX346264B_D0336.tif" />

in which Zt is independently selected each time it appears from O, S, NH, or CH₂, Z₂ is independently selected each time it appears from N or CH, Z₃ is independently selected each time it appears from N or CH, Z₄ is independently selected each time it appears from O, S, NH, or CH₂, and W_1t W₂, W₃, W₄, W₅ and W₆ each are independently selected each time they appear from CH or N. A and B

IMPI

MEXICAN INSTITUTE

OF THE PROMEOAD

INDUSTRIAL

<img file="MX346264B_D0337.tif" />

116 are each independently optionally substituted with one or more R_TO.

More preferably, A is selected from

<img file="MX346264B_D0338.tif" />

or

<img file="MX346264B_D0339.tif" />

y is optionally substituted with one or more R_TO; B is selected from

<img file="MX346264B_D0340.tif" />

or

<img file="MX346264B_D0341.tif" />

in which Z_1t Z₂, Z₃, Z₄, Wi, W₂, W₃, W₄, W₅, W₆ they are as defined above. Preferably Z₃ is N and Z₄ is NH. For example. A can be selected from

<img file="MX346264B_D0342.tif" />

eg,

<img file="MX346264B_D0343.tif" />

<img file="MX346264B_D0344.tif" />

), and is optionally substituted with one or more R_TO;

<img file="MX346264B_D0345.tif" />

(for example,

<img file="MX346264B_D0346.tif" />

117

IMPI

INSTITUTE MB1CANO

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0347.tif" />

<img file="MX346264B_D0348.tif" />

Also preferably, A is

<img file="MX346264B_D0349.tif" />

(for example,

<img file="MX346264B_D0350.tif" />

which A 'and B' are independently selected from carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, and A and B independently are optionally substituted with one or more R_to.

More preferably, A is

<img file="MX346264B_D0351.tif" />

, B is

<img file="MX346264B_D0352.tif" />

, and A and B are substituted with one or more halogens, such as F or Cl. When A and / or B are benzimidazole substituted with halogen (for example, A is

<img file="MX346264B_D0353.tif" />

<img file="MX346264B_D0354.tif" />

118

IMPI

INSTITUTO MEXICANO · * M RIOPIIDA · INDUSTRY *.

the compounds of Formula l_B they may have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype 1a mutants, compared to the same compounds but with unsubstituted benzimidazole.

Preferably D is selected from carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is optionally substituted with one or more R_TO. Preferably D can also be selected from C ^ Cs alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, and is optionally substituted with one or more substituents selected from R_L. More preferably, D is carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is substituted with one or more R_m, in which 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_TO. More preferably, D is phenyl, and is substituted with one or more R_M, in which Rm is as defined above. Quite preferably,

<img file="MX346264B_D0355.tif" />

above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they can also be preferably halogen such as F.

<img file="MX346264B_D0356.tif" />

119

D is also preferably pyridinyl, pyrimidinyl, or

IMPI

INSTTTVTO MSJtCANO

MUrtqnttMa

INMSTWIM thiazolyl, optionally substituted with one or more R_TO. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or more R_M.

Rather preferably, D is

Rm

<img file="MX346264B_D0357.tif" />

ΛΛΛ /

<img file="MX346264B_D0358.tif" />

<img file="MX346264B_D0359.tif" />

in which Rm is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they may also preferably be halogen such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, and is optionally substituted with one or more R_TO. Most preferably D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, or benzo [d] [1,3] dioxol-5-yl, and is substituted with one or more R_M Of

<img file="MX346264B_D0360.tif" />

<img file="MX346264B_D0361.tif" />

120

<img file="MX346264B_D0362.tif" />

MPI

Νςρτυτ · μμκμ * · 'Μ IMPUSTRIAL PROPERTY

<img file="MX346264B_D0363.tif" />

, and is optionally substituted with one or more

Rm

Preferably R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CvCg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, or carboxy. Rather preferably, R_M is C alkyl_rC₆ which is optionally

<img file="MX346264B_D0364.tif" />

IMPI

121

IMDUJTJUAL 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, in which L_s is a C, -C bond or alkylene₆, and R_AND is -N (R_SR_S'), -OR_s, -C (O) R_S, -C (O) OR_S, -C (O) N (R_SR_S'), -N (Rs) C (O) R_s', -N (Rs) C (O) OR_s', -N (R_s)SW₂R_s', -SO₂R_s, -MR_s, or -P (O) (ORs)₂, in which R_s and Rs' may, for example, each be independently selected each time they appear from (1) hydrogen or (2) C-alkyl_;-C₆optionally substituted each occurrence with one or more halogen, hydroxy, -O-Ci-C alkyl₆ or 3-6 membered heterocycle; or R_m is Ci-Cq alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ -Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or

-N (RsRs') 0® most preferred, R_M is halogen (for example,

<img file="MX346264B_D0365.tif" />

IMPI

<img file="MX346264B_D0366.tif" />

122

DiM fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or alkyl of 0_Γ0₆ (e.g., methyl, isopropyl, tert-butyl), C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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_S-R_AND in which L_s is a link and R_ANDis -N (R_sRs '), -O-Rs, -N (Rs) C (O) ORs', -N (Rs) SO₂Rg ', -SO₂Rs, or -SRg. For example in cases where L_s is a link, R_AND is -NíalquiKCíC₆))₂ (for example, -NMe₂); -N (alkylene (Ci-C₆) -O-Ci-C alkyl₆) 2 (for example -N (CH₂CH₂OMe)₂); -N (alkyl (C - C₆) (rent (C₁-C₆Ci-C) -Oalkyl₆) (for example -N (CH₃) (CH₂CH₂OMe)); -O-Ci-C alkyl_B (for example, -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-halogenoalkyl of Ο, -Cg (for example, -OCF₃, -OCH₂CF₃); -O-alkylene (Ci-C₆) -piper¡na (for example, -O-CH₂CH₂-1-piper¡lo); -NyalkylKC ^ CejCÍOjO-Cí-Cg alkyl (for example, -N (CH₃) C (O) OCH₂CH (CH₃)₂), -N ((C₁-C₆)SW₂-Ci-Cg alkyl (for example, -N (CH₃)SW₂CH₃); -SW₂-C ^ Cg alkyl (for example, -SO₂I); -SW₂-C ^ Cg halogenoalkyl (for example, -SO₂CF₃); or -S-halogenoalkyl of CpCg (e.g. SCF₃). Also preferably R_M is -L_s-Re in which L_s is C alkylene_rC_s (for example, -CH₂-, -C (CH₃)₂-, -C (CH₃)₂-CH₂-) and R_and is -O-Rs, -C (O) ORs, -N (R_S) C (O) OR_S', or -P (O) (OR_s)₂. For example R_M is -alkylene-Cg) OR_s (for example, -C (CH₃)₂-CH₂-OMe); -alkylene ^ -C ^ -C (O) OR_S

IΜ Ρ1. _ _ MEXICAN INSTITUTE

123 &lt;SS ^ (for example, -C (CH₃)₂-C (O) OMe); -alquiteníCj-CgJ-NtRsJCíOjORs' (for example, -C (CH₃) 2-CH2-NHC (O) OCH₃); o -alkylene ^ -Cg) P (O) (OR_s) 2 (for example, -CH₂-P (O) (OEt)₂). Also more preferably R_M is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj-Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (RsRs') For example R_M is cycloalkyl (for example, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (for example, morpholin-4-yl, 1,1-dioxydothomorpholin-4- yl, 4-methylpiperazin-1-yl, 4-methoxycarbonlpiperazin-1-lo, pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperazin-1-lo, 3,5-d¡methylp¡per¡d¡n-1-yl, 4,4difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6 (dimethylamino) p¡ ridin-3-lo). Rather preferably, R_M is C alkyl_rCg 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 carbocycle of C₅-C₆, 5- to 6-membered heterocycle or 6 to 12-membered bicyclo and is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more

IMPI • «πτυτο MtaucANo

Say THE I4OF1EDAD rwsm: u

<img file="MX346264B_D0367.tif" />

124

R_to. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, in which said carbocycle of C₃-C₆ or 3-6 membered heterocycle independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of Cy-C₆, C2-C alkenyl₆₁ C alkynyl₂-C₆, Cy-C haloalkyl_6&gt;C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) ORs or -N (RsRs'), and J may also be optionally substituted with one or more R_to. Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably, J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cy-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Cy-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs') Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is 6 to 12 membered bicycles (for example, a fused 7 to 12 membered bicycles, with bridged or spiro structure that

<img file="MX346264B_D0368.tif" />

125

IMPI

O6LA0R HBDA »WOUSTWia · comprises a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_TO. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 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-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

<img file="MX346264B_D0369.tif" />

-N (RsRs') - Preferably, D is, in which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C_6&gt; 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,

IMPI

<img file="MX346264B_D0370.tif" />

126 nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C_6&gt; C alkynyl₂-C₆, Ci-Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C_6t C (O) OR_S or

INDUSTRIAL

<img file="MX346264B_D0371.tif" />

-N (RsRs') - Also preferably, D is, in which each R_n is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Also d

J preference, D is, and J is carbocycle of C₃-C₆ or 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3- to 6-membered heterocycle which in a way

IMPI

<img file="MX346264B_D0372.tif" />

127 independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ -Ce haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S’).

X is preferably carbocycle of C₅-C₆, 5 «λΑλλ heterocycle

I to 6 members, or 6 to 12 member bikes (for example, '--o ”—'1, in which X₃ is N and is directly linked to

-L₃-D), and is optionally substituted with one or more R_TO or R_F. Non-limiting examples of X are described earlier in the present application.

Lí and L₂ preferably they are independently bond or alkylene of CvCg, L₃ preferably selected from bond, CrC alkylene₅ or -C (O) -, and Li, L₂, and L₃ are each independently optionally substituted with one or more R_l. More preferably, Li, L₂ and L₃ are each independently Ci-C bond or alkylene₆ (for example, -CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Quite preferably, L ^ L₂ and L₃ they are link.

<img file="MX346264B_D0373.tif" />

128

R₂ and Rs, taken together with the atoms to which they

IMPI ^{, NST}nyroi &lt;BucANo ^D* ^W.5 P^{M £ Dad} 'NDDSTRlAt are attached, preferably form a 5- to 6-membered heterocycle

<img file="MX346264B_D0374.tif" />

or 6 to 12 membered bike (for example, ¹ which is optionally substituted with one or more R_TO. Rg and R12 taken together with the atoms to which they are attached, preferably form a 5 to 6 membered heterocycle or 6 to 6 membered bicyclo

<img file="MX346264B_D0375.tif" />

optionally substituted with one or more R_TO.

-TR_d'can, without limitation, be independently selected each time it appears from -C (O) -Ly'-R_d', -C (O) OL_Y'-R_d', -C (O) -L_Y'-N (R_b)CABBAGE_s”-R_d', -C (O) -L_Y'-N (R_b) C (O) OL_s”-R_d', -N (R_b) C (O) -Ly'-N (R_b) C (O) -Ls ”-Rd ', -N (Rb) C (O) -Ly'N (Rb) C (O) OL_s”-Rd '&gt; or -N (Rb) C (O) -Ly'-N (Rb) -L_s”-Rd ', in which L_AND'is each independently L_s'and, preferably, each is independently C ^ Cg alkylene (e.g.

-CH₂-

<img file="MX346264B_D0376.tif" />

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

<img file="MX346264B_D0377.tif" />

129

IMPI

IIUTI1UI MEXICAN

M THE industrial PROPERTY

-TR_d'Each Vé¿ que dpaieee is independently selected from -C (O) -L_Y'-M'-L_s"-Rd 'or -N (Rb) C (O) -L_Y'-M'-Ls ”-Rd' · More preferably, -TR_D'is selected independently each time it appears from -C (O) -L_Y'-N (R_b) C (O) -Ls ”-Rd 'or -C (O) -L_Y'-N (R_b) C (O) OL_s”-Rd '. Rather preferably, -TR_D'is selected independently each time it appears from -C (O) -L_Y'-N (R_b) C (O) -R_d'or -C (O) -L_Y'-N (R_b) C (O) OR_d', in which L_AND'preferably each is independently Cn-Cg alkylene (e.g. -CH₂- o) and is optionally substituted with one or more substituents selected from R_L.

R_c'is preferably hydrogen, and R_or'preferably is selected independently each time it appears from R_AND. More preferably, R_D'is independently selected each occurrence from C ^ Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-membered heterocycle; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally substituted each time it appears with one or more substituents listed below.

<img file="MX346264B_D0378.tif" />

130

IMPI

IMTflyro MKICANO

DCUM PIEDAD INDUSTRIAL selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Ra is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Cí-Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, 0 alkyl_Γ0₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; or -L_TO-OR_S, -L_TO-MR_s, -L_TO-C (O) R_S, -L_TOOC (O) R_S, -L_to-C (O) OR_s, -La-N (RsRs'), -L_to-S (O) R_s, -L_to-SW₂R_s, -L_toC (O) N (R_SR_S'), -L_to-N (R_s) C (O) R_s', -L_to-N (R_s) C (O) N (R_s'R_s”), -L_toN (R_s)SW₂Rs', -L_to-SW₂N (R_sRs'), -L_to-N (R_s)SW₂N (R_s'Rs ”), -L_toN (Rs) S (O) N (R_s'Rs ”), -L_to-OS (O) -Rs, -L_to-BEAR)₂-R_s, -L_to-SW)₂OR_s, -L_to-S (O) ORs, -L_to-OC (O) OR_s, -L_to-N (Rs) C (O) OR_s', -L_to-OC (O) N (R_sR_s'), -L_to-N (R_s) S (O) -Rs', -L_to-S (O) N (R_sR_s') or -L_to-C (O) N (R_s) C (O) -R_s', in which L_TO is bond, Cí-Cg alkylene, C alkenylene₂-C₆ or

IMPI ^{, Ν5Τ}ΠΡΤ ° Μ · ΟΟΛΛΟ

M THE CURRENCY

INDUSTRY!

<img file="MX346264B_D0379.tif" />

131

More preferably, R_TO is halogen, hydroxy, C alkynylene₂-C₆.

mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Rather preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CC alkyl₅, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 they are each independently selected each time they appear from the link; or CrCg alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆·

<img file="MX346264B_D0380.tif" />

132

A and B can be the same or different. Similarly,

L, and L₂ They can be the same or different.

<img file="MX346264B_D0381.tif" />

<img file="MX346264B_D0382.tif" />

, and is optionally substituted with one or more

<img file="MX346264B_D0383.tif" />

substituted with one or more R_TO; and D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ο, -Οβ alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'). and J may also be optionally substituted with one or more R_TO. Preferably D

133

<img file="MX346264B_D0384.tif" />

IMPI

MSXICAN INSTITUTE

OF THE «ΟΡΙΙΒΛΠ industrial

<img file="MX346264B_D0385.tif" />

defined above.

Also preferably, D is

<img file="MX346264B_D0386.tif" />

<img file="MX346264B_D0387.tif" />

, in which J and R_N they are as defined above.

Ζϊ is independently selected each time it appears from O, S, NH, or CH₂; and Z₂ is independently selected each time it appears from N or CH. Preferably, A is

<img file="MX346264B_D0388.tif" />

they are substituted with one or more halogens, such as F or Cl.

When A and / or B are halogen substituted benzimidazole (for example,

A is

<img file="MX346264B_D0389.tif" />

), compounds of this embodiment may have significantly improved pharmacokinetic properties as well as inhibitory activity

134 IMPI »

ΙΝΤΓΠνΤΟ MMCANO »55 &lt;» βΚ5

MU non HMD W- n *. INDUSTRIAL W j improved against certain HCV genotype 1a mutants, compared to the same compounds but with unsubstituted benzimidazole. Lj and L₂ are each independently Ci-C bond or alkylene₆, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and

L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_Y'-N (Rb) C (O) -L_s”-Rd 'or -C (O) -L_Y'N (R_b) C (O) OL_s”-R_d', in which L_AND'is C - C alkylene₆ (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -TR_D'may also, without limitation, be selected from -C (O) -L_Y'-Ls ”-Rd'&gt; -C (O) -L_Y'-O-Ls ”-Rd'&gt; -C (O) -Ly'-N (R_b) -Ls ”R_d', or -C (O) -L_Y'-N (Rb) S (O)₂-Ls ”-Rd'-

<img file="MX346264B_D0390.tif" />

and is optionally substituted with one or more R_to (eg halogen); B is' q, and is optionally substituted with one or more R_TO (eg halogen); and D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle

<img file="MX346264B_D0391.tif" />

135

IMPI

M »nVK&gt; M« UCANO

D »IA INDWSTRIAt OWNED BY C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C - C alkyl_AND, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C_s, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Of

<img file="MX346264B_D0392.tif" />

as defined above. Also preferably, D is

<img file="MX346264B_D0393.tif" />

in which J and R_N they are as defined above. When A and / or B are halogen substituted benzimidazole (e.g. A is

<img file="MX346264B_D0394.tif" />

Compounds of this embodiment may have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype 1a mutants, compared to the same compounds but with unsubstituted benzimidazole. M and L₂ are each independently Ci-C bond or alkylene₆. and L₃ is bond, C ^ Ce alkylene or -C (O) -, and L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L-ι, L₂, and L₃ they are link. -TR_d'is selected independently each time it appears from -C (O) -L_AND'-N (R_B)CABBAGE_s”-R_d'or -C (O) -L_Y'-N (Rb) C (O) OL_s”-Rd ', in which L_AND'is C ^ Ce alkylene (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -T-Rd 'can also, without limitation, be selected from -C (O) -L_AND'-L_S”-R_D', -C (O) -L_AND'-OL_S”-R_D', -C (O) -L_Y'-N (Rb) -Ls ”-Rd', or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-R_d'. R₂ and R₅₎Taken together with the atoms to which they are attached, they preferably form a 5- to 6-membered heterocycle or 6-membered bicyclo (e.g.,) which is optionally substituted with one or more R_TO. 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 bicyclo

<img file="MX346264B_D0395.tif" />

137

IMPI

MEXICAN INSTITUTE

OF INDUSTRY PROPERTY (members (by optionally

<img file="MX346264B_D0396.tif" />

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

<img file="MX346264B_D0397.tif" />

which is optionally substituted with one or more R_TO; Rg and Ri₂, taken together with the atoms to which they are attached, form

<img file="MX346264B_D0398.tif" />

which is optionally substituted with one or more R_TO.

Even in another embodiment of this aspect, A is

<img file="MX346264B_D0399.tif" />

optionally substituted with one or more

Ra (preferably A is substituted with at least one halogen such as F); B is

<img file="MX346264B_D0400.tif" />

, and is optionally substituted with one or more R_to (preferably B is substituted with at least one

<img file="MX346264B_D0401.tif" />

138

<img file="MX346264B_D0402.tif" />

IMPI

INSTITUTE ΜβΠΓΑΝΟ DE LAFROMEDAD INDUSTRIA!

halogen such as F).

in which X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_TO or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_to. J is carbocycle of

C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, 10-15 membered tricycle or 13-15 membered carbocycle / heterocycle, and J is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, halogenoalkyl of CrCe halogenoalkenyl of C₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_sRs'), or (2) trimethylsilyl, -OR_s, -MR_s or -C (O) R_S; and J may also be optionally substituted with one or more R_TO. Preferably, D is

<img file="MX346264B_D0403.tif" />

<img file="MX346264B_D0404.tif" />

139 j, in which J is as defined above, and each R_Nis independently selected from R_D and is preferably hydrogen or halogen such as F. L, and L₂ are each independently bond or alkylene of Ο, -Οβ, and L₃ is bond, Ci-C alkylene₆ or -C (O) -, and L-ι, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably L ,. L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'N (R_b)CABBAGE_s”-Rd 'or -C (O) -L_Y'-N (Rb) C (O) OL_s”-Rd '&gt; in which L_AND'is alkylene of Ο, -Οβ (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_l, and L_s"Preferably link. -T-Rd 'can also, without limitation, be selected from -C (O) -L_AND'-L_S”-R_D', -C (O) -L_Y'-OL_s”-Rd ', -C (O) -L_Y'-N (R_b) -L_s”-R_d', or -C (O) -L_Y'-N (R_b)SW)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-membered bicyclo (eg X or \) which is optionally substituted with one or more R_TO. R₉ and R₁₂, taken together with the atoms to which they are attached, preferably

<img file="MX346264B_D0405.tif" />

140 form a 5- to 6-membered heterocycle or bic ^ Fcfb dé β d W

IMPI

INSTITUTO MEXICANO • E LA MONEDAD industrial members (for example,

<img file="MX346264B_D0406.tif" />

or

<img file="MX346264B_D0407.tif" />

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

<img file="MX346264B_D0408.tif" />

which is optionally substituted with one or more R_TO; R₉ and Ri₂, taken together with the atoms to which they are attached, form

<img file="MX346264B_D0409.tif" />

which is optionally substituted with one or more R_TO.

In yet another aspect, the present also features compounds of Formula I._c and pharmaceutically acceptable salts thereof.

<img file="MX346264B_D0410.tif" />

c in which:

141

IMPI

IMS MUI · MEXICAN INDUSTRIAL PROPERTY

Rnb is Rbí

R_c'each is independently selected from R_c;

R_d'each is independently selected from R_D;

R₂ and Rs, 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_TO;

R₉ and R₁₂, 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_TO;

A, B, D, X, Li, L₂, L_3i T, R_to, R_b, R_c, and R_D are as previously described in Formula I.

In this regard, A is preferably C carbocycle.₅-C₆or 5- to 6-membered heterocycle, and is optionally substituted with one or more R_TO; and B is preferably 8 to 12 membered bicyclo (such as and is optionally substituted with one or more R_TO. Z₁ is O, S, NH or CH₂; Z₂ is N or CH; Z₃is N or CH; Z₄ is O, S, NH or CH₂; and W_1f W₂, W₃₁ W₄, W₅ and W₆ each is independently selected from CH or N.

More preferably, A is phenyl (eg,), and is optionally substituted with one or more R_TO; and B

<img file="MX346264B_D0411.tif" />

IMPI msinuio mixican m la noniBAD

INDUSTRIAL

142

<img file="MX346264B_D0412.tif" />

<img file="MX346264B_D0413.tif" />

, and is optionally substituted with one or more R_TO, in which Zi, Z₂, Z₃, Z₄, W-, W₂, W₃,

W₄, W₅₎ W₆ they are as defined above. Preferably Z₃ is N and Z₄ is NH.

For example, B can be

<img file="MX346264B_D0414.tif" />

<img file="MX346264B_D0415.tif" />

N

<img file="MX346264B_D0416.tif" />

N

NH

<img file="MX346264B_D0417.tif" />

NH and is optionally substituted with one or more

Ra Also preferably, A is carbocycle of C₅-C₆ (For example, phenyl such as

<img file="MX346264B_D0418.tif" />

) or 5- to 6-membered heterocycle;

<img file="MX346264B_D0419.tif" />

<img file="MX346264B_D0420.tif" />

which B 'is selected from carbocycle of C₅-C₆ or 5- to 6-membered heterocycle. A and B independently are optionally substituted with one or more R_TO.

Preferentially D is selected from carbocycle of

143

<img file="MX346264B_D0421.tif" />

C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles,

IMPI

ΙΝΓΓΓΓυτβ MEXICAN

OF INDUSTRIAL PROPERTY and is optionally substituted with one or more R_TO. Preferably D can also be selected from Ci-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, and is optionally substituted with one or more substituents selected from R_l. More preferably, D is carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is substituted with one or more R_m, in which 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_TO. More preferably, D is phenyl, and is substituted with one or more R_M, in which R_m it is as defined above. Quite preferably,

<img file="MX346264B_D0422.tif" />

above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they can also preferably be halogen such as F.

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

144

<img file="MX346264B_D0423.tif" />

<img file="MX346264B_D0424.tif" />

one or more R_M.

IMPI

XSTTTWTO MEXICAN INDUSTRIAL PROPERTY

Rather preferably, D is ^rm_

N ^ N) = N or Y''N ^KN | ^KN1

ΛΛΛ / ₍ Or k / WV, in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they may also preferably be halogen such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, and is optionally substituted with one or more R_TO. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, or benzo [d] [1,3] dioxol-5-yl, and is substituted with one or more R_M. Of

<img file="MX346264B_D0425.tif" />

<img file="MX346264B_D0426.tif" />

, or

<img file="MX346264B_D0427.tif" />

, and is optionally substituted with one or more

Rm

145

<img file="MX346264B_D0428.tif" />

IMPI

INSTITUTE ΜΜΚΛΝΟ t ΙΛ M »PTEDAX&gt; in» ustiuai

Preferably R_M it is halogen, hydrnyi. mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 6-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono , thioxo, formyl, cyano, CiC alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, or carboxy. Rather preferably, R_M is C alkyl_rC₆ 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_AND, in which L_s is a bond or alkylene of

<img file="MX346264B_D0429.tif" />

146 IMPI

ΙΝΠΠνΤ · MEXICAN

OF THE NORITY

INDUSTRIAL

CrC₆, and Re is -N (R_SR_S'), -OR_s, -C (O) R_S, -C (O) OR_S, -C (O) N (R_sRs'), -N (R_S) C (O) R_S', -N (R_S) C (O) OR_S', -N (R_s)SW₂R_s', -SO₂R_s, -MR_s, or -P (O) (OR_s)₂, in which R_s and Rs' may, for example, each be independently selected each occurrence from (1) hydrogen or (2) Cy-C alkyl₆optionally substituted each occurrence with one or more halogen, hydroxy, -O-Cy-C alkyl₆ or 3-6 membered heterocycle; or R_M is Cy-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, Phosphono, thioxo, formyl, cyano, Cy-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Cy-C haloalkyl₆, C halogenoalkenyl₂-C_and, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (RsRs') - More preferably, R_M is halogen (for example fluoro, chloro, bromine, iodine), hydroxy, mercapto, amino, carboxy, or Cy-Ce alkyl (for example methyl, isopropyl, tert-butyl), C alkenyl₂-C_s or C alkynyl₂-C₆, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen,

147 IMPIAS

WSTITWO MEXICANO í LA ntOKERÁD MTÍ · bwstrial M g * 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_s-Re in which L_s is a link and R_ANDis -N (RsRs'), -OR_s, -N (R_S) C (O) OR_S', -N (R_s)SW₂Rs', -SO₂R_s, or -SR_s. For example in cases where L_s is a link, R_AND is -N (Ci-C alkyl₆) 2 (for example, -NMe₂); -NfalquilentC ^ Cej-O-C alkyl₁-C₆)₂(for example -N (CH₂CH₂OMe)₂); -N (alkyl (Ci-C₆) ((Ci-Cg) -O C ^ Cg alkyl) (for example -N (CH₃) (CH₂CH₂OMe)); -O-C ^ Cg alkyl (eg -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-C ^ Cg halogenoalkyl (for example, -OCF₃, -OCH₂CF₃); -O-alkylene (Ci-C₆) -piperidine (for example, -O-CH₂CH₂-1-piperdyl);

-NylalkylKCj-CgjCíOjO-Ci-C alkyl₆ (for example, -N (CH₃) C (O) OCH₂CH (CH₃)₂), -N ((C₁-C₆)SW₂-alkyl of C ^ Cg (for example, -N (CH₃)SW₂CH₃); -SW₂-C ^ Cg alkyl (for example, -SO₂I); -SW₂-Ci-Cg halogenoalkyl (e.g. -SO₂CF₃); o -C halogenoalkyl_rC₆ (for example, SCF₃). Also preferably R_M is -L_S-R_AND in which Ls is Cí-Cg alkylene (e.g., -CH₂-, -C (CH₃)₂-, -C (CH₃)₂-CH₂-) and R_AND is -OR_s, -C (O) OR_S, -N (R_s) C (O) ORs', or -P (O) (OR_S)₂. For example R_M is -alkylene C ^ Cg) O-Rs (for example, -C (CH₃)₂-CH₂-OMe); -alkylene-Ci-CgJ-C (O) OR_S(for example, -C (CH₃)₂-C (O) OMe); -alkylene (C₁-C_s) -N (R_s) C (O) OR_s'(for example, -C (CH₃)₂-CH₂-NHC (O) OCH₃); or -alq uilen (Ci-Cg) P (O) (OR_s) 2 (for example, -CH₂-P (O) (OEt)₂). Also more preferably R_M is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally ¹⁴⁸ IMPI ^

INSTITUTE M1UCANO

OBLA HDRIDAD

INDUSTRIAL substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_rC₆C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (RsRs'). For example R_M is cycloalkyl (for example, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (for example, morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1 -i lo, 4-methoxy carbon i lpiperazin-1 -i lo, pyrrolidin-1 -i lo, piperidin-1-yl, 4-methylpiperid¡n-1-yl, 3,5-dimethylp¡ peridin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6 (dimethylamino) pyridin-3-yl). Rather preferably, R_M is Ci-C alkyl₆ 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 carbocycle of C₅-C₆, 5- to 6-membered heterocycle or 6 to 12-membered bicyclo and is substituted with J and optionally substituted with one or more R_to, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, in which said carbocycle of C₃-C₆ or independently 3-6 membered heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, ¹⁴⁹ IMPI ^

MEXICAN INSTITUTE

MUKOFfMa ÍtWI iWDurnM nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CrCg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆0--0 haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_to. Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably, J is at least substituted with one carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C, -C alkyl_AND, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ -Cg haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'). Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is 6 to 12 membered bicycles (for example, a fused 7 to 12 membered bicycles, bridged or spiro structure comprising a nitrogen ring atom through which J is covalently bonded to D) and is optionally substituted with one or more R_to. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆, 3- to 6-membered heterocycle or 6 to 12-membered bicyclo and

<img file="MX346264B_D0430.tif" />

C (O) OR_S or θ2 "θ6&gt;

<img file="MX346264B_D0431.tif" />

r_n

N

150 IMPI

MEXICAN INSTITUTE

M THE PROPERTY

INDUSTRIAL, is optionally substituted with one or more R¿. and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 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, C ^ Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-Cg, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, haloalkynyl

R_n

Rn

-N (RsRs') · Preferably, D is which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 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, C - C alkyl₆₎C alkenyl₂-C₆, C alkynyl₂-C₆, Cj-Cg haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

IMPI iwsiirirro Mexican

M THE industrial PROPERTY

<img file="MX346264B_D0432.tif" />

151

<img file="MX346264B_D0433.tif" />

each R_n is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is substituted with a carbocycle of C₃-C₆ or 3-6 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-C alkyl₆, C alkenyl₂-C_s, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Also preferably, D is

<img file="MX346264B_D0434.tif" />

, and J is carbocycle of C₃-C₆ or 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3- to 6-membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, ¹⁵² IMPI ^

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL formyl, cyano, Cí-Ce alkyl, C alkenyl₂-Cb, alkynyl

C₂-Cb, C, -C haloalkyl_6! C halogenoalkenyl₂-Cb, C haloalkynyl₂-C₆, C (O) OR_S or -N (R_sRs')

X is preferably carbocycle of Ο₅-Ο₆, 5 to 6-membered heterocycle, or 6 to 12-membered bicycles (for example, σννν 'νΑΛ&gt;

Μ Μ '1 ο ® — J, in which Χ₃ is Ν and is directly linked to -L₃-D), and is optionally substituted with one or more R_TO or R_F. Non-limiting examples of X are described earlier in the present application.

Lt and L₂ preferably they are independently bond or alkylene of 0ι-0₆₎ L₃ preferably selected from bond, CpCe alkylene or -C (O) -, and L₄, L₂, and L₃ are each independently optionally substituted with one or more R_l. More preferably, Li, L₂ and L₃ are each independently Ci-Ce bond or alkylene (e.g., -CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Rather preferably, L_1t L₂ and L₃ they are link. L₁ and L₂ They can be the same or different.

R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or § Μ^νί · My or bicycle with 6 to 12 members (for example, x 0 7.)

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0435.tif" />

153 which is optionally substituted with one or more R_TO. R_g and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6-membered bicyclo (for

<img file="MX346264B_D0436.tif" />

) which is optionally substituted with one or more R_TO.

-TR_d'can, without limitation, be independently selected each time it appears from -C (O) -L_AND'-R_D', -C (O) OL_Y'-R_d', -C (O) -L_AND'-N (RB) C (O) -L_S”-RD^,, -C (O) -L_AND'-N (R_B) C (O) OL_s”-R_d', -N (R_b)CABBAGE_Y'-N (R_b) C (O) -Ls ”-Rd ', -N (R_b)CABBAGE_Y'N (R_b) C (O) OL_s”-R_d', or -N (Rb) C (O) -L_Y'-N (RB) -L_s”-Rd ', in which L_AND'is each independently L_s'and, preferably, each is independently Ci-C alkylene₆ (for example,

-CH₂- o) and optionally substituted with one or more substituents selected from R_l. Preferably -TR_d'is selected independently each time it appears from -C (O) -L_Y'-M'-L_s"-Rd 'or -N (Rb) C (O) -L_Y'-M'-L_s”-Rd'- More preferably, -TR_d'is selected independently each time it appears from -C (O) -L_Y'-N (R_b)CABBAGE_s”-Rd 'or -C (O) -L_Y'-N (Rb) C (O) OL_s”-R_d'. Rather preferably, -TR_D'is selected independently each time it appears from the Mexican institute

OF THE industrial PROPERTY of -C (O) -Ly'-N (R_b) C (O) -R_d'or -C (Q1-Lv'-NÍR_p1CíO) OR_d', in which L_AND'preferably each is independently C, -C alkylene₆ (for example, -CH₂- o / X) and optionally substituted with one or more substituents selected from Rl ·

Rnb and Rc 'are preferably hydrogen, and R_D'preferably is selected independently each time it appears from R_AND- More preferably, R_D'is independently selected each occurrence from Ct-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-6 membered heterocycle; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Ce alkyl, C alkenyl₂-C_6l C alkynyl₂-C₆, C halogenoalkyl_rC₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

R_to preferably it is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or alkyl of

155

IMPI

C ^ Ce, C alkenyl₂-C₆ or C alkynyl₂-C₆, rarixjinf.rio ir ^ maiAp is independently optionally substituted each time it appears with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C, -C halogenoalkyl_and, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; or -L_TO-OR_S, -L_TO-MR_s, -L_TO-C (O) R_S, -L_TOOC (O) R_S, -L_to-C (O) OR_s, -L_to-N (R_sRs'), -L_to-S (O) R_s, -L_to-SW₂R_s, -LaC (O) N (Rs^Rs'), -L_to-N (R_s) C (O) Rs', -L_to-N (Rs) C (O) N (R_s'R_s”), -L_toN (R_s)SW₂R_s', -L_to-SW₂N (R_sR_s'), -L_to-N (R_s)SW₂N (Rs'Rs ”), -l_toN (R_s) S (O) N (R_s'Rs ”), -L_to-OS (O) -R_s, -L_to-BEAR)₂-R_s, -L_to-SW)₂OR_s, -L_to-S (O) OR_s, -L_to-OC (O) OR_s, -L_to-N (R_s) C (O) OR_s', -L_to-OC (O) N (R_sR_s'), -L_to-N (R_s) S (O) -R_s', -L_to-S (O) N (R_sR_s') or -L_to-C (O) N (R_s) C (O) -R_s', in which L_to is bond, Οί-Οβ alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆.

More preferably, R_to is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C ^ Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents

<img file="MX346264B_D0437.tif" />

156

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPERTY selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Rather preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C ^ -Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted 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 they are each independently selected each time they appear from the link; or CrCg alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆.

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

<img file="MX346264B_D0438.tif" />

, and is optionally substituted with one or more

<img file="MX346264B_D0439.tif" />

157

IMPI Mexican institute Dt LA property INRUSTWAL

Ra, in which Zi is O, S, NH or CH₂; and Z₂ is N or CH. D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle (e.g. phenyl), and is optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_to. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl,

<img file="MX346264B_D0440.tif" />

C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (RsRs'), and J may also be optionally substituted with one ^RNv

R_n or more R_to. Preferably, D is which R_M and Rn are as defined

<img file="MX346264B_D0441.tif" />

as defined above. Lí and L₂ are each independently Ci-Ce bond or alkylene, and L₃ is bond, alkylene

158 IMPI ^ * «wmrroμlaican of the MtenEnA»? * »_ 'RarWx

Industrial Οτ-Οδ or -C (O) -, and L_1f L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably Li, L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'-N (R_B)CABBAGE_s”-R_d'or -C (O) -L_Y'-N (R_b) C (O) OL_s”-Rd ', in which L_AND'is C ^ Cg alkylene (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -TR_D'may also, without limitation, be selected from -C (O) -L_Y'-L_s”-Rd ', -C (O) -L_Y'-OL_s”-Rd ', -C (O) -L_Y'-N (R_b) -Ls ”-Rd '. or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-Rd '· Preferably, R₂ and R₅, taken together with the atoms to which these

<img file="MX346264B_D0442.tif" />

which is optionally substituted with one or more R_TO; Rg and R12, taken together with the atoms to which they are attached, form

<img file="MX346264B_D0443.tif" />

which is optionally substituted with one or more R_TO.

In another embodiment of this aspect, A is phenyl (eg,

<img file="MX346264B_D0444.tif" />

), and is optionally substituted with one or more

R_to (preferably A is substituted with at least one halogen such as F); and B is

<img file="MX346264B_D0445.tif" />

and is optionally substituted

IMPI ^

159 MEXICAN INSTITUTE

DEIAPR PIEDAD

INDUSTRIAL with one or more R_TO (Preferably, B is substituted with a halogen such as F). X is '---', in which X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_TO or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_TO. J is carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, 10-15 membered tricycle or 13-15 membered carbocycle / heterocycle, and J is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Cs alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_sRs'), or (2) trimethylsilyl, -OR_s, -MR_s or -C (O) R_S; and J can also be optionally j

substituted with one or more R_TO. Preferably, D is Uw or

IMPI

160 tNSTIlUl »MBCICANO DE LA PROPERTY INDUSTRIAL y Jw, in which J is as defined above, and each Rn is independently selected from R_D and is preferably hydrogen or halogen such as F. Lt and L₂ are each independently bond or alkylene of Οτ-Ce, and L₃ is bond, alkylene of Ο ^ Οβ or -C (O) -, and L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_n L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'N (Rb) C (O) -Ls ”-R_d'or -C (O) -L_Y'-N (R_b) C (O) O-Ls ”-Rd ', in which L_AND'is C alkylene_rC₆ (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -TR_D'may also, without limitation, be selected from -C (O) -L_AND'-L_S”-R_D', -C (O) -L_Y'-OL_s”-Rd ', -C (O) -L_Y'-N (Rb) -L_s”-Rd ', or -C (O) -L_Y'-N (Rb) S (O)₂-Ls ”-Rd'- Preferably, R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic (eg *) or 6 to 12-membered bicyclic ring (eg, which is optionally substituted with one or more R_TO; R₉ and R12, taken together with the atoms to which they are attached,

161

<img file="MX346264B_D0446.tif" />

form a 5- to 6-membered heterocyclic ring (for

IMPI

INSTITUT MEXICANO DE LA PROPIEDAD INDUSTRIAL example,

<img file="MX346264B_D0447.tif" />

) or 6 to 12-membered bike (eg,

<img file="MX346264B_D0448.tif" />

which is optionally substituted with one or more R_TO.

In yet another aspect, the present invention includes compounds of Formula I._D and pharmaceutically acceptable salts thereof.

D

<img file="MX346264B_D0449.tif" />

in which:

G and and G₂ are each independently selected from carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more R_TO;

R_c'each is independently selected from R_c;

R_d'each is independently selected from R_D;

R₂ and R₅, taken together with the atoms to which these

1 «IMPI ^ · ΐ IIUI · MHRCANO DI LA ηΟΠΕΟΛ» '· tNDVSTWAL * * are united, form a 3 to 12 membered heterocycle which is optionally substituted with one or more R_TO;

Rg and R₁₂₎ Taken together with the atoms to which they are attached, they form a 3- to 12-membered heterocycle which is optionally substituted with one or more R_TO;

A, B, D, X, Ln L₂, L₃, T, R_TO, R_c, and Rd are as previously described in Formula I.

In this regard, A and B are preferably independently selected from carbocycle of C₅-C₆ or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more R_to. More preferably, at least one of A and B is phenyl (eg * / \ | * \ = / *), and is optionally substituted with one or more R_TO. Quite preferably, both A and B are each independently phenyl (eg, \ = / '), and are each independently optionally substituted with one or more R_TO.

Preferably D is selected from carbocycle of C₅-C₆, 5- to 6-membered heterocycle, or 8 to 12-membered bicyclo, and is optionally substituted with one or more R_TO. Preferably D can also be selected from C ^ -Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, and is optionally substituted with one or more R_L. More preferably, D is carbocycle of C₅-C₆, 5 to 6 membered heterocycle, or 6 to 12 membered bicycles, and is ¹⁶³ IMPI ^ institui · Mexican Wjf¹

DAYNOTNESS vV .¾

IMDVSTW! · '-Substituted with one or more R_M, in which R_M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_S-R_AND. Also preferably, D is phenyl, and is optionally substituted with one or more R_TO. More preferably, D is phenyl, and is substituted with one or more

Rm, in which R_M it is as defined above. By way of

R .. Rm

<img file="MX346264B_D0450.tif" />

rather preferred, D is, (ΛΛΛ / O t / WW, O in which R_M is as defined above, and each R_N is independently selected from R_D and is preferably hydrogen. One or more R_N they can also be preferably halogen such as F.

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

Rather preferably, D is

<img file="MX346264B_D0451.tif" />

<img file="MX346264B_D0452.tif" />

«/ Ww

<img file="MX346264B_D0453.tif" />

, in which R_M is as defined above, and each R_N is selected independently of

IMPI

INSTITUTE mexican

M THE CURRENCY »

INDUSTRIAL

<img file="MX346264B_D0454.tif" />

164 from R_D and is preferably hydrogen. One or more R_N they may also preferably be halogen such as F. D is also preferably indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, or indazolyl, and is optionally substituted with one or more R_TO. Most preferably D is indanyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, or benzo [d] [1,3] dioxol-5-yl, and is substituted with one or more R_M. Of

<img file="MX346264B_D0455.tif" />

<img file="MX346264B_D0456.tif" />

-OR

OR

Λ / W jy is optionally substituted with one or more preference, R_M is halogen, hydroxy, mercapto, amino, oxo, phosphonoxy, phosphono, thioxo, cyano; or alkyl of

Ci-C₆, C alkenyl₂-C_s or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more

IMPI «TOUTOMÉXICAN *

<img file="MX346264B_D0457.tif" />

165 substituents selected from halogen, hydroxy, 'mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, or carboxy. Quite preferably Rm is C ^ Cg alkyl 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_AND, in which L_s is a Ci-Cg bond or alkylene, and R_AND is -N (R_SR_S'), -OR_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)SW₂R_s', -SO₂R_s, -MR_s, or -P (O) (OR_s&gt; 2. in which R_s and Rs' may, for example, each be independently selected each time they appear from (1) hydrogen or (2) C-alkyl_rC₆optionally substituted each occurrence with one or more halogen, hydroxy, -O-Ci-C alkyl₆ or 3-6 membered heterocycle; or R_M is C ^ Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is

<img file="MX346264B_D0458.tif" />

'·· IMPI

KSnrUTU MEMCANO

MLAnOPKBAD • «OUSTUAL optionally substituted 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC alkyl_and, C alkenyl₂-C₆, C alkynyl₂-C₆, Cj-Ce haloalkyl, C haloalkenyl₂-C₆₎ C halogenoalkynyl₂-C₆, -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 C-alkyl_rC₆ (e.g., methyl, isopropyl, tert-butyl), C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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_s-Re in which L_s is a link and R_andis -N (R_SR_S'), -OR_s, -N (R_S) C (O) OR_S', -N (R_s)SW₂R_s', -SO₂R_s, or -SR_s. For example in cases where L_s is a link, R_AND en -NíalquiKCT C₆))₂ (for example, -NMe₂); -N (alkylene (C₁-C_B) -O-C alkyl₁-C₆)₂(for example -N (CH₂CH₂OMe)₂); -NyalkylKCi-CeHalkyleneCT-CeJ-OC ^ Cealkyl) (for example -N (CH₃) (CH₂CH₂OMe)); -O-Ce-Ce alkyl (e.g. -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n167

<img file="MX346264B_D0459.tif" />

hexyl); -O-Ci-C halogenoalkyl₆ (for eiemnln -OCF ^. -OCFkCFa); -O-alkylene (Ci-C₆) -piperidine (for example, -O-CH₂CH₂-1 -piperidyl); -N (alkyl (Ci-C₆) C (O) O-alkyl of C ^ -Cs (for example, -N (CH₃) C (O) OCH₂CH (CH₃)₂), -N ((C₁-C₆)SW₂-Ci-C alkyl₆ (for example, -N (CH₃)SW₂CH₃); -SW₂-C ^ Ce alkyl (for example, -SO₂I); -SW₂-C ^ Ce halogenoalkyl (for example, -SO₂CF₃); or -C- | -C halogenoalkyl₆ (for example, SCF₃). Also preferably R_M is -L_s-Re in which L_s is C alkylene_rC₆ (for example, -CH₂-, -C (CH₃)₂-, -C (CH₃)₂-CH₂-) and Re is -OR_s, -C (O) OR_S, -N (R_S) C (O) OR_S', or -P (O) (OR_s)₂For example R_M is -alkylene (C ^ Ce) OR_s (for example, -C (CH₃)₂-CH₂-OMe); -alkylene C ^ Cej-C (O) OR_S(for example, -C (CH₃)₂-C (O) OMe); -alkylene (C₁-C₆) -N (R_S) C (O) OR_S'(for example, -C (CH₃)₂-CH₂-NHC (O) OCH₃); or -alq υϋβηίΟτ-C₆) P (O) (OR_s) 2 (for example, -CH₂-P (O) (OEt)₂). Also more preferably R_M is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CtCs alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, 0 halogenoalkyl_Γ0_6;C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S, or -N (RsRs'). For example R_m is cycloalkyl (for example, cyclopropyl, 2,2-dichloro-1-methylcycloprop-1-yl, cyclohexyl), phenyl, heterocyclyl (for example, morpholin-4-yl, 1,1-dioxidothiomorpholin-4-it, 4-methylpiperazine -1-yl, 4-methoxycarbonylpiperazin-1 -yl, pyrolid i n-1 -yl,

168

<img file="MX346264B_D0460.tif" />

piperid in -1 -i lo, 4-methylpiper¡d¡n-1 -yl, 3,5-dimethylpiperidin-1-¡lo, 4,4IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY difluoropiperidin-1-yl, tetrahydropyran-4-yl, pyridinyl, pyridiη-3-yl, 6 (dimethylamine) pyridin-3-yl). Rather preferably, R_M is Ci-C alkyl₆ 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 carbocycle of C₅-C₆, 5- to 6-membered heterocycle or 6 to 12-membered bicyclo and is substituted with J and optionally substituted with one or more R_to, in which J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_to. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, in which said carbocycle of C₃-C₆ or 3-6 membered heterocycle independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CrCs, C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl, C-haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'). and J may also be optionally substituted with one or more R_to. Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably, J is at least ¹⁶⁹ IMPI »

INSTITUTO MIXICANO ot la nomoAo C ^^ 3B

INDUSTRIAL - substituted with a carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ο alkyl_ΓΟ₆, C alkenyl₂-C₆, C alkynyl₂-C₆, haloalkyl, -Ce, C haloalkenyl₂-C₆₁C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs') Also preferably, D is carbocycle of C₅-C₆ or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_to, and J is 6 to 12 membered bicycles (for example, a fused 7 to 12 membered bicycles, bridged or spiro structure comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_to. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_TO, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 membered heterocycle which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ο, -Οβ alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆.

C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

<img file="MX346264B_D0461.tif" />

J

-N (RsRs'). Quite preferably, D is ^ Lz, in which each R_N is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆, 3-6 membered heterocycle or 6-12 membered bicyclo and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3- to 6-membered heterocycle 10 which independently is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , Cy-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Cy-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or

J

-N (RsRs'). Also preferably, D is, in which each Rn is independently selected from R_D and is preferably hydrogen or halogen, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is substituted with a carbocycle of C₃-C₆ or 3 to 6 membered heterocycle which independently is optionally substituted with one or more 25 substituents selected from halogen, hydroxy,

171 IMPI ^

MEXICAN INSTITUTE

OF PROREDAD J

INDUSTRIAL mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Cj-Cg alkyl, C alkenyl₂-C₆, alkynyl

C₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_SR_S'), and J may also be optionally substituted with one or more R_TO. Also from

J preference, D is rfyw, and J is carbocycle of C₃-C₆ or 3- to 6-membered heterocycle and is optionally substituted with one or more R_TO, and preferably J is at least substituted with one carbocycle of C₃-C₆ or 3-6 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-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Cg haloalkyl, C haloalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs') X is preferably carbocycle of C₅-C₆, 5- to 6-membered heterocycle, or 6 to 12-membered bicycles (for example,

\ ..... / or VJ, in which X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_TO or R_F. Non-limiting examples of X are described above

172

<img file="MX346264B_D0462.tif" />

in the present application.

IMPI

INSTITUTO MEXICANO Dt LA PROritPAD INDUSTRIA!

L-ι and L₂ preferably they are independently Ct-Cg bond or alkylene, L₃ preferably selected from bond, CfCg alkylene or -C (O) -, and L₂, and L₃ are each independently optionally substituted

R_l. More preferably, L_1t L₂ and L₃ are each with one or more independently Cl-C bond or alkylene₆ (for example, -CH₂- or

-CH2CH2-), and are each independently optionally substituted with one or more R_L. Rather preferably, L_1f L₂ and l_₃ they are link.

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 bicyclo (for example, '

<img file="MX346264B_D0463.tif" />

which is optionally substituted with one or more R_TO.

R9 and Ri2&gt; taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle

Y — No. 6 to 12-membered bike (for example, \

<img file="MX346264B_D0464.tif" />

which is optionally substituted with one or more R_TO.

G1 and G₂ preferably each of

<img file="MX346264B_D0465.tif" />

173

H

N.

<img file="MX346264B_D0466.tif" />

independently from

IMPI 'N instttuto mixkmno ní LA FReMÍDA »

<img file="MX346264B_D0467.tif" />

HN-m

<img file="MX346264B_D0468.tif" />

, and are each independently is substituted with one or more R_TO (for example, one

More preferably, Gi is tautomer thereof), and G₂ is

NH or more chlorine (including (including or bromine).

any any tautomer thereof), and each G, and G₂ independently is optionally substituted with one or more R_TO (for example, one or more chlorine or bromine).

-TR_d'can, without limitation, be independently selected each time it appears from -C (O) -L_AND'-, -C (O) OLy'-Rd', -C (O) -Ly'-N (R_b)CABBAGE_s”-Rd ', -C (O) -Ly'-N (R_b) C (O) O-Ls ”-Rd ',

-N (R_b)CABBAGE_Y^,-N (Rb) C (O) -Ls ”-Rd ', -N (R_b)CABBAGE_Y'-N (R_b) C (O) OL_s”R_d', or -N (R_b)CABBAGE_Y'-N (Rb) -L_s”-Rd ', in which L_AND'is each independently L_s'and, preferably, each is independently Ci-C alkylene₆ (for example, -CH₂- or

<img file="MX346264B_D0469.tif" />

174 IMPI ^

MEXICAN INSTITUTE

DEALAHOnEBA »

INDUSTRIAL and optionally substituted with one or more substituents selected from R_L. Preferably, -T-Rd 'is selected independently each time it appears from -C (O) -L_AND'-M'L_s'' -Rd 'or -N (R_b)CABBAGE_Y^,-M^,-L_s”-R_d'. Most preferably -TR_d'is selected independently each time it appears from -C (O) -L_Y'-N (R_b)CABBAGE_s”-Rd 'or -C (O) -L_Y'-N (R_b) C (O) OL_s”Rd'- Quite preferably, -TR_d'is selected independently each time it appears from -C (O) -L_AND'-N (R_B) C (O) R_d'or -C (O) -L_Y'-N (R_b) C (O) OR_d', in which L_AND'preferably each is independently C ^ Cg alkylene (e.g.

-CH₂- o / X) and optionally substituted with one or more substituents selected from R_l.

R_c'is preferably hydrogen, and R_D'preferably is selected independently each time it appears from R_and. More preferably, R_D'is independently selected each time it appears from Cí-Ce alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , carbocycle of C₃-C₆ or 3-6 membered heterocycle; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which independently is optionally

175

<img file="MX346264B_D0470.tif" />

substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,

IMPI

Μ1ΧΚΛΝΟ INSTITUTE OF INDUSTRIAL PROPERTY nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Cu-Ce haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Ra is preferably halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or CfCe alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_;-C₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆; or -L_TO-OR_S, -L_TO-MR_s, -L_TO-C (O) R_S, -L_TOOC (O) R_S, -La-C (O) OR_s, -La-N (RsRs'), -L_to-S (O) R_s&gt; -L_to-SW₂R_s, -L_toC (O) N (R_sRs'), -L_to-N (Rs) C (O) R_s', -L_to-N (R_s) C (O) N (Rs'R_s”), -L_toN (R_s)SW₂R_s', -La-SO₂N (R_sRs'), -La-N (R_s)SW₂N (R_s'Rs ”), -L_toN (R_s) S (O) N (Rs'R_s”), -L_TO-OS (O) -R_s, -L_to-BEAR)₂-R_s, -L_to-SW)₂OR_s, -La-S (O) OR_s, -La-OC (O) OR_s, -L_to-N (R_s) C (O) OR_s', -L_to-OC (O) N (R_sR_s'), -L_to-N (R_s) S (O) -Rs', -L_to-S (O) N (R_sRs') or -L_to-C (O) N (Rs) C (O) -Rs', in the

176 industrial which L_TO is bond, C alkylene_rC₆ C alkenylene₂-C₆ or C alkynylene₂-C₆.

More preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C &lt;-C alkyl₆, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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 carbocycle of C₃-C₆ or 3- to 6-membered heterocycle, each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cg alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, CrCe haloalkyl, C haloalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆.

Rather preferably, R_TO is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C ^ Cg alkyl, C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is 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 .

Ls. L_s'and L_s"Preferably they are each independently selected each time they appear from the link; or

177 IMPIAS

MEXICAN INSTITUTE

DI LA Λ «ΗΕ DA»

KBUSTMAL C - C alkylene_{S |} C alkenylene₂-C₆ or C alkynylene₂-C₆A and B can be the same or different. Similarly,

L! and L₂ they 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_TO; D is phenyl, and is independently optionally substituted with one or more R_TO, or is substituted with J and optionally substituted with one or more R_TO, in which J is carbocycle of C₃-C₆, 3-membered heterocycle or 6 to 12-membered bicyclo and is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆ or 3-6 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, C alkyl_rC₆, C alkenyl₂-C₆, C alkynyl₂-C₆, C ^ Ce halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, C (O) OR_S or -N (R_sRs'), and J may also be optionally substituted with one or more R_TO; and G-ι is

<img file="MX346264B_D0471.tif" />

and every G and G₂ independently are optionally substituted with one or more R_TO (for example, one or more

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0472.tif" />

178

<img file="MX346264B_D0473.tif" />

in which R_M and Rn are as defined above. As well

<img file="MX346264B_D0474.tif" />

previously. Li v L₂ are each of ^RN \

Rn ^ preferably, D is as defined independently bond or alkylene of Ο ^ Οβ, and L₃ is bond, C alkylene_rC₆ or -C (O) -, and L-ι, L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_1f L₂, and L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_AND'-N (R_B)CABBAGE_s”-R_d'or -C (O) -L_Y'-N (R_b) C (O) OL_s”-R_d', in which L_AND'is C ^ Ce alkylene (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -TR_D'may also, without limitation, be selected from -C (O) -L_AND'-L_S”-R_D', -C (O) -L_Y'-OL_s”-Rd ', -C (O) -L_Y'-N (R_b) -L_s”-Rd ', or -C (O) -L_Y'-N (R_b)SW)₂-L_s”-Rd '. Preferably R₂ and Rs, taken together with the atoms to which they are attached, form

<img file="MX346264B_D0475.tif" />

which is optionally substituted

<img file="MX346264B_D0476.tif" />

179 with one or more R_TO; R₉ and R12, taken together with the atoms at which

IMPI

MEXICAN INSTITUTE

M THE INDUSTRIAL PROMISE which these are united, form X. which is optionally substituted with one or more R_TO.

In another embodiment of this aspect, A and B are each independently phenyl (eg, * \ - /), and are each independently optionally substituted with one or more R_TO (Preferably, A and B are each independently optionally substituted with at least one halogen such as F). X is \, in which X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_TO or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_TO. J is carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, 10-15 membered tricycle or 13-15 membered carbocycle / heterocycle, and J is optionally substituted with one or more R_TO. Preferably, J is substituted with a carbocycle of C₃-C₆, 3-6 membered heterocycle, 6-12 membered bicyclo, or 7-12 membered carbocycle / heterocycle, which independently is optionally substituted with one or more substituents selected from (1) halogen, hydroxy,

IMPI

<img file="MX346264B_D0477.tif" />

180

ΙΜΓΠΤυΤ »MEXICAN MLAPItOMEBAB IMMSTMAl mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ^ Ce alkyl, C alkenyl₂-C₆, C alkynyl₂-C₆, Ci-C haloalkyl₆, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -C (O) OR_S or -N (R_SR_S'), or (2) trimethylsilyl, -OR_s, -MR_s or -C (O) R_S; and J can also be optionally j^Rn\ /TO. /^Rntt Rn Rn substituted with one or more R_TO. Preferably, D is -A or

J, in which J is as defined above, and each R_Nis independently selected from R_D and is preferably hydrogen or halogen such as F.

<img file="MX346264B_D0478.tif" />

<img file="MX346264B_D0479.tif" />

and every Gt and G₂ independently is optionally substituted with one or more R_TO (for example, one or more chlorine or bromine). L, and L₂ are each independently bond or alkylene of Ct-Ce, and L₃ is bond, Ci-C alkylene₆ o -C (O) -, and Ln L₂, and L₃ each independently is optionally substituted with one or more R_L. Preferably, L ^, L₂, and mmnn «M * icANo

ΜΜΡΜΝΜΑ »iwrlthual X ^ w

181

L₃ they are link. -TR_D'is selected independently each time it appears from -C (O) -L_Y'-N (Rb) C (O) -L_s”-Rd 'or -C (O) -L_Y'N (Rb) C (O) O-Ls ”-Rd', in which L_AND'is CiC alkylene₆ (for example, -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s"Preferably link. -T-Rd 'may also, without limitation, be selected from -C (O) -Ly'-Ls ”-Rd'&gt; -C (O) -Ly'-O-Ls'-Rd ', -C ( O) -Ly'-N (Rb) -Ls ”R_d', or -C (O) -Ly'-N (R_b)SW)₂-Ls ”-Rd '. Preferably R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,

<img file="MX346264B_D0480.tif" />

) or 6 to 12 membered bike (for example,

<img file="MX346264B_D0481.tif" />

which is optionally substituted with one or more R_TO; Rg and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (for example,%^&lt; ) or 6 to 12 membered bicycles (eg, \) which is optionally substituted with one or more RaΕπ in another aspect, the present invention includes compounds having Formula l_AND and pharmaceutically acceptable salts thereof,

<img file="MX346264B_D0482.tif" />

182

IMPI

INSTITUTO MEXICANO DILAHIOMEDA »t &lt;DU $ TMA *

D ^L3

I

YAL₁ X I-2 BZ

Ie in which:

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

Ly and L₂ are each independently selected from Cy-C bond or alkylene_and which independently is optionally substituted each time it appears with one or more halogen, hydroxy, -O-Cy-C alkyl₆, u -Ohalogenoalkyl of Cy-C₆;

Ls is Cy-C bond or alkylene₆;

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

<img file="MX346264B_D0483.tif" />

in which Zy is independently selected each time it appears from O, S, NH, or

CH₂, Z₃ is independently selected each time it appears from N or CH, and Wy, W₂, and W₃ they are each independently selected each time they appear from CH or N; A and B are each independently optionally substituted with one or more R_TO.

D is carbocycle of C₆-C₁₀ or 5 to 12 membered heterocycle, each of which is optionally substituted with

<img file="MX346264B_D0484.tif" />

183 one or more R_M;

Y is -T'-CCR ^ zJNÍRsJ-T-Rd;

Z is -T'-C (R₈R₉) N (R₁₂) -TR_D;

Rt is hydrogen, Cn-Cg alkyl, CrCe haloalkyl, or 3- to 6-membered carbocycle or heterocycle, in which each of said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted each time it appears with one or more substituents selected from halogen, Ci-C alkyl₆, C ^ Cg haloalkyl, -O-Ci-C alkyl₆ or -O-C ^ Cg halogenoalkyl;

R₂ and R₅ are each independently hydrogen, Οη-Cg alkyl, Ci-Cg haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each of said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C ^ Cg alkyl, Οτ-Cg haloalkyl, -O-Ci-C alkyl₆ u -Ohaloalkyl of C- | -C₆; or 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_TO(for example, 1, 2, 3, or 4 R_TO);

R₈ is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each of said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted each time

Mexican IMPI iwrmrro

OF THE MIOME DA »

DiDUSTKUL

<img file="MX346264B_D0485.tif" />

184 appears with one or more substituents selected from halogen, C ^ Cg alkyl, Ο ^ Οβ haloalkyl, -O-Cf-Cg alkyl or -O-Ci-C haloalkyl₆;

R₉ and R₁₂ are each independently hydrogen, C ^ -Ce alkyl, C ^ Cg haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each of said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted each occurrence with one or more substituents selected from halogen, C alkyl_rC₆, C ^ Cg haloalkyl, -O-Ci-C alkyl₆ or - C ^ Cg halogenoalkyl; or R₉ and R_12l Taken together with the atoms to which they are attached, they form a 3- to 12-membered heterocycle which is optionally substituted with one or more R_TO(for example, 1, 2, 3, or 4 R_TO);

T is independently selected each time it appears from bond or -C (O) -L_S’-;

T 'is independently selected each time it appears from bond, -C (O) N (R_B) -, -N (R_B) C (O) -, or 3- to 12-membered heterocycle, in which said 3- to 12-membered heterocycle is independently optionally substituted each time it appears with one or more R_TO;

R_d each is independently selected each time it appears from hydrogen or R_TO;

R_TO is independently selected each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo,

IMPI ^lwy»Rtm&gt; MmcA_Wor

OS THE INDUSTRIAL RUBBING

<img file="MX346264B_D0486.tif" />

185 cyano, or -L_s-R_and;

Rb and Rb 'are each independently selected each time they appear from hydrogen; or C ^ Ce alkyl which independently is optionally substituted at each occurrence with one or more substituents selected from halogen or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; in which each 3- to 6-membered carbocycle or heterocycle in R_B or R_B'independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, Ci-C alkyl₆, Ci-C haloalkyl₆C ^ Ce, -Oalkyl, or -O-Ci-C haloalkyl₆;

R_and is independently selected 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 (RsRs'), -N (R_S) C (O) R_S', -N (R_s) C (O) N (R_s'Rs'). -N (Rs) SO₂Rs', -SO₂N (R_sR_s),

-N (Rs) SO₂N (R_s'R_s”), -N (Rs) S (O) N (R_s'Rs ”), -OS (O) -R_s, -BEAR)₂-R_s&gt;-SW)₂OR_s, -S (O) OR_s, -OC (O) OR_s, -N (R_s) C (O) OR_s', -OC (O) N (R_sRs'). -N (R_s) S (O) -R_s', -S (O) N (R_sR_s'), -C (O) N (R_s) C (O) -Rs', o = C (R_sR_s'); or Oí-Ce alkyl, C alkenyl₂-C_s or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of

C₃-C₁₂ or heterocycle of 3 to 12 members, each of which of

<img file="MX346264B_D0487.tif" />

186

IMPI

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY is independently optionally substituted each time it appears with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of Ο, -Οθ, C alkenyl₂-C₆, C alkynyl₂-C₆, CC haloalkyl₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆;

R_l is independently selected each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -SR_s, -C (O) R_S, -OC (O) R_S, -C (O) OR_S, -N (R_SR_S'), -S (O) R_s, -SO₂R_s, -C (O) N (R_sRs'), or -N (R_s) C (O) R_s'; or carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Ce alkyl, C alkenyl₂-Ce, C alkynyl₂-C₆, C-C haloalkyl₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆;

L_s is selected independently each time it appears from link; or C ^ Cg alkylene, C alkenylene₂-C_and or C alkynylene₂-C₆, each independently optionally substituted with halogen;

L_s'is selected independently each time it appears from link; or C.-Cg alkylene, C alkenylene₂-C₆ or C alkynylene₂-C₆, each of which independently is optionally substituted each time it appears

<img file="MX346264B_D0488.tif" />

187

IMPI

MEXICAN INSTITUTE

OSLA inbustrjal PROPERTY with one or more R_L;

Rs, Rs' and Rs "are each independently selected each time they appear from hydrogen; C alkyl_rC_6! C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano , -O-C ^ Cg alkyl, -O-C ^ Cg haloalkyl, or 3- to 12-membered carbocycle or heterocycle; or 3- to 12-membered carbocycle or heterocycle; in which each 3- to 12-membered carbocycle or heterocycle in R_s, Rs' or R_s"Independently is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, alkyl of CrC₆, C alkenyl₂-C₆, C alkynyl₂-C₆, geno haloalkyl_ΓΟ₆, C halogenoalkenyl₂-C₆ or halogenoalkynyl of C₂-C₆;

R_m is selected independently each time it appears from:

halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF₅, -N (R_SR_S'), -OR_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)SW₂R_s', -S (O) R_s, -SO₂R_s, -S (O) N (R_sRs'), -SR_s, -Yes (R_s)₃, or -P (O) (OR_S)₂;

C alkyl_rC₆, C alkenyl₂-C₆ or C alkynyl₂-C₆,

IMPI Mexican institute

DI M INDUSTRIAL PROPERTY

<img file="MX346264B_D0489.tif" />

188 each of which is independently optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -N (R_sRs'), -OR_s, -OC (O) R_S, -OC (O) ORs, -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)SW₂R_s', -S (O) R_s, -SO₂R_s, -S (O) N (R_sRs'), -SR_s, or -P (O) (OR₈)₂O

G_2i in which G₂ is a carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more Rg2&gt; and each R_G2 is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C alkyl₆, C alkenyl₂-C₆, C alkynyl₂-C₆, Οτ-Οβ halogenoalkyl, C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -OR_s, -C (0) 0R_s, -C (O) R_S, -N (RsRs'), or -L₄-G₃;

L₄ is a bond, Cí-Ce alkylene, C alkenylene₂-C₆, C alkynylene₂-C₆, -O-, -S-, -N (R_B) -, -C (O) -, -S (O)₂-, -S (O) -, -0 (0) 0-, -OC (O) -, -OC (O) O-, -C (O) N (R_b) -, -N (R_b)CO)-,

-N (R_b) C (O) O-, -OC (O) N (R_b) -, -N (R_b) S (O) -, -N (R_b)SW)₂-, -S (O) N (R_b) -, -S (O)₂N (R_b) -, -N (R_b) C (O) N (R_b') -, -N (Rb) SO₂N (R_b') -, or

-N (R_b) S (O) N (R_b’)-;

G₃ is a carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_G3; Y

R_G3 is each independently, each time

<img file="MX346264B_D0490.tif" />

IMPI

INSTITUTO MEXICANO de la ntonioA »industrial

189 appear, halogen, -C-C alkyl₆, -C (O) -CtCo alkyl, -Ci-Chaloalkyl₆, -O-C alkyl_rC₆Ci-Ce, -O-halogenoalkyl, C carbocycle₃-C₆, or 3-6 membered heterocycle.

As described earlier in the present application for the compounds of Formula I_AND A and B are each phenyl, pyridinyl, thiazolyl, or

<img file="MX346264B_D0491.tif" />

is independently selected each time it appears from O, S, NH, or

CH₂, Z₃ is independently selected each time it appears from N or CH, and Wi, W₂, and W₃ each is selected independently each time they appear from CH or N¡

A and B are each independently optionally substituted with one or more R_TO.

Preferably, A is selected from phenyl (for. / "Λ,^Ν~ Λ

I saw W ri example, \ = / '), pyridinyl (e.g. * \ = / $), thiazolyl

<img file="MX346264B_D0492.tif" />

<img file="MX346264B_D0493.tif" />

Preferably, B is selected from phenyl (for

<img file="MX346264B_D0494.tif" />

190

<img file="MX346264B_D0495.tif" />

<img file="MX346264B_D0496.tif" />

IMPI

INSTITUTO MEXICANO, DE LA PROPERTY INDUSTRIAL example,), pyridinyl (for example,), thiazolyl

<img file="MX346264B_D0497.tif" />

<img file="MX346264B_D0498.tif" />

), and is optionally substituted with one or more R_TO.

Quite preferably both A and B are phenyl w X-4 M (for example, both A and B are \ - / ^? ); or A is \ - / 'and

<img file="MX346264B_D0499.tif" />

<img file="MX346264B_D0500.tif" />

which each A and B independently is optionally substituted with one or more R_to.

In certain embodiments of this aspect of the invention, A and B are substituted with one or more R_TO, in which each R_TO is independently selected from halogen (for

<img file="MX346264B_D0501.tif" />

191

IMPI

MEXICAN MSTITWTO

OF INDUSTRIAL PROPERTY example, fluoro, chloro), L_S-R_AND (in which L_s it is emphasis and r_AND is -Ci-C alkyl₆ (for example, methyl), -OR_s (for example, -O-C ^ Ce alkyl, -OCH₃), or -Ct-Cg alkyl optionally substituted with one or more halogens (e.g. -CF₃)), or L_S-R_AND (in which L_s is C alkylene_rC₆ and R_AND is -OR_s (e.g., -alkylKCTCg) - © Ci-C alkyl₆, -CH₂OCH₃)). For example, in certain modalities A

<img file="MX346264B_D0502.tif" />

and B is as defined in the present application above. In

<img file="MX346264B_D0503.tif" />

<img file="MX346264B_D0504.tif" />

192

IMPI

INSTITUTO MEXICANO • E la mOHlDAD MMCTRIA1

<img file="MX346264B_D0505.tif" />

As described in the present application above for compounds of Formula I_AND, D is carbocycle of C₆-C₁₀ or 3- to 12-membered heterocycle optionally substituted with one or more R_m. Preferably, D is aryl of C₆-C₁₀ (eg, phenyl, naphthyl, indanyl), or 5 to 10 membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, benzo [d] [ 1,3] dioxol-5-yl), and D is substituted with one or more R_m. For example, in certain embodiments D is preferably phenyl substituted with one or more R_M, in which each R_M is independently halogen (eg fluoro, chloro, bromo); Ci-C alkyl₆ (eg, tert-butyl); Cy-C alkyl₆ substituted with one or more halogens (e.g. CF₃); -OR_s such as -O-alkyl of Cy^-C @ (for example, -O-CH₂CH₃); u -O-Cy-C alkyl₆ substituted each time it occurs with one or more halogens (e.g. -OCF₃, -O-CH₂CHF₂) u -O-Cy-C alkyl₆ (for example, -OCH₂CH₂OCH₃); -O-Rs (for example, -O-Cy-C alkyl₆, such as -OCH₂) substituted with 3- to 12-membered heterocycle (eg, 3-ethyloxetan-3-yl, 1,3-dioxolan-4-yl); -OR_s in which R_s is an optionally substituted 3- to 12-membered carbocycle or heterocycle (eg, cyclopentyl, cyclohexyl, phenyl, 1,3-dioxan-5-yl); -N (R_s) C (O) Rs' in which R_s and Rs' are each independently Cy-C alkyl₆ (eg, -N (t-Bu) C (O) Me); SF₅;

<img file="MX346264B_D0506.tif" />

193

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

-SW₂Rs in which R_s is C ^ Ce alkyl (for example, -SO₂I); or carbocycle of C₃-C₁₂ (eg cyclopropyl, cyclohexyl, phenyl).

In certain embodiments of this aspect of the invention, D is preferably phenyl or pyridyl and is substituted with one or more R_Min which an R_M is G₂. In certain embodiments in which D is phenyl or pyridyl, D is substituted with G₂, G₂ is 3- to 12-membered heterocycle (eg pyridinyl, piperidinyl, pyrolidinyl, azetidinyl, oxazolyl) and is optionally substituted with one or more halogens (eg fluoro, chloro), hydroxy, oxo, cyano , Cf-Cs alkyl (e.g., methyl), C alkenyl₂-C₆, C alkynyl₂-C₆, halogenoalkyl of geno, -Οβ (e.g. CF₃), C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C_and, -O-C ^ Ce alkyl (for example, -O-CH₃), -C (O) OR_S (for example, -C (O) OCH₃), -C (O) Rs (for example, -C (O) CH₃), or -N (RsRs'); and D is optionally also substituted with one or more R_M in which R_M is halogen (e.g. fluoro, chloro), C- | -C alkyl₆ (for example, methyl), Cf-Οβ haloalkyl (for example, CF₃), or -O-C ^ Ce alkyl (for example, -O-CH₃). In some other embodiments D is phenyl or pyridyl and G₂ is, 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_G2 in which L₄, G₃ and R_G2 they are as defined in the present application. L₄, for example, is a bond, a Ci-C alkylene₆ (for example, -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, etc.), -O-, or -S (O)₂-, G₃ is for example a carbocycle of C₃-C₁₂ optionally substituted with one or more R_G3. R_G2 and R_G3 they are each

IMPI mjTmnw mbucano

MMHVntTY

IMBUmUAL

<img file="MX346264B_D0507.tif" />

194 independently each time halogen appears,

-C (O) -Co-Ce alkyl, -Cf-Ce alkyl, -CiC halogenoalkyl₆,

-O-Ci-Ce 0-0 'alkyl or -O-halogenoalkyl. In certain

N ^x N modalities G₂ is, in which is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrolid ini lo, piperidinyl, piperazinyl) attached to the parent molecular moiety through a nitrogen atom and substituted with one or two L₄-G₃ and is optionally substituted with one or more R_G2- Therefore, in certain modalities in which L₄ is a

<img file="MX346264B_D0508.tif" />

link, G₂ is 74, in which it is optionally substituted with R_G2 and G₃ is optionally substituted with R_G3. Thus,

<img file="MX346264B_D0509.tif" />

It can be, for example, 3-phenylazet¡d¡n-1-yl, 3-phenylpyrrolidin1-¡lo, 4-phenylp¡peraz¡n-1-yl, 4-phen¡lpiper¡d¡n-1 -yl, 4-phenyl-3,6d ih id ropyrid in-1 (2H) -i lo, 4,4-dipheni Ipipe rid in-1 -i lo, 4-acetyl-4-phenylpiperidin-1 -yl, 4- ( 4-methoxyphenyl) piperidin-1-lo, 4- (4-fluorophenyl) piper¡d¡n-1-yl, or 3-phenylpiperidin-1-yl, and in which D may also be optionally substituted with one or more R_M (by

IMPI

<img file="MX346264B_D0510.tif" />

VrnVl * MMKANO miZmopisimd nreumiAL

195 example, fluoro, chloro, methyl, methoxy).

In some other embodiments of this aspect of the invention, L₄ is an alkylene of CtCs,

<img file="MX346264B_D0511.tif" />

,^g3

-O-, or -S (O)₂-, and G₂ is

<img file="MX346264B_D0512.tif" />

in which 'X is as defined above and is optionally substituted with R_G2 and G₃ is as defined above and is optionally substituted with R_G3. Thus,

<img file="MX346264B_D0513.tif" />

It can be, for example, 4-tosylpiperazin-1-yl, 4-phenoxypiperidin-1-yl, 3-phenoxypyrrol¡d¡n-1-yl, 4-benzylpiper¡d¡n-1-¡lo, 4phenethylpiperidin -1-yl, or 3-phenylpropyl) piperidin-1-yl.

In some other embodiments of this aspect of the invention, D is phenyl or pyridyl, D is substituted with G₂ and G₂ is a spiro, bridged, or fused carbocycle or bicyclic heterocycle optionally substituted with L₄-G₃ and one or more R_G2, in which D is optionally substituted with one or more R_M and Rm, L₄, G₃, and R_G2 they are as defined in the present application. In certain

IN 'Μ G modes₂ is, in which is a heterocycle

<img file="MX346264B_D0514.tif" />

<img file="MX346264B_D0515.tif" />

IMPI

<img file="MX346264B_D0516.tif" />

196 imnyro «mucan · DI LA ntOMMAD INDUSTRIAL nitrogenous bicyclic spiro, with bridged structure, or fused (for example, 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct-2yl, 6 -azaspiro [2.5] oct-6-yl, octahydro-2H-isoindol-2-yl, 3azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa -8azaspiro [4.5] dec-8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with G₃ and one or more R_G2- Therefore, G₂ is 3-azabicyclo [3.2.0] hept-3-yl, 2azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [2.5] oct-6-yl, octahydro-2Hisoindol-2-yl, 3- azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2yl, or 1,4-dioxa-8-azaspiro [4.5] dec-8-¡lo¡ L₄ is a bond and D is optionally substituted with one or more R_M (eg fluoro, chloro, methyl, methoxy).

In certain embodiments of this aspect of the invention, D

Rm

<img file="MX346264B_D0517.tif" />

r is X in which R_M is as defined above in relation to Formula l_AND, and D is optionally substituted with one or more R_M

Rm

<img file="MX346264B_D0518.tif" />

additional. For example, in cases where D is 4 «, R_M can be fluoro, chloro, tert-butyl, -O-CH₂CH₃, -O-CF₃, -O-CH₂CHF₂, -O-CH₂CH₂OCH₃, -O-CH₂- (3-ethyloxetan-3-yl), -O-CH₂- (1,3-dioxolan-4yl), -O-cyclop nthyl, -O-cyclohexyl, -O-phenyl, -O- (1,3-dioxan-5-yl),

<img file="MX346264B_D0519.tif" />

197

IMPI

ΙΝΓΠΤυΤΟ MEXICAN DC THE INDUSTRY PROPERTY L cyclopropyl, cyclohexyl, phenyl, SF₅, -SO₂Me, or -N (t-Bu) C (O) Me and D may be optionally substituted with one or more R_M additional which are selected from the group consisting of halogen (e.g. fluoro, chloro) and Ο alkyl_ΓΟ₆ (for example, methyl).

Rm A τ

In certain embodiments, D is X in which 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 with one or more R_M Additional which are selected from the group consisting of halogen (eg, fluoro, chloro) and alkyl CvCs (eg, methyl).

Rm

<img file="MX346264B_D0520.tif" />

In certain modalities, D is X in et which R_M is cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted with one or more R_M Additional which are selected from the group consisting of halogen (eg, fluoro, chloro) and Ci-Cg alkyl (eg, methyl).

R «

<img file="MX346264B_D0521.tif" />

In certain embodiments, D is X in which R_M that-

<img file="MX346264B_D0522.tif" />

198

IMPI

INSTITUTO MEXICANO Dt LA RROMIDAD INDUSTRIAL

CH2- (3-ethyloxetan-3-yl), -O-CH₂- (1,3-dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, or -O- (1,3-dioxan-5-yl) and D is optionally substituted with one or more R_M Additional elements that are selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C alkyl₆ (for example, methyl).

g₂

In certain embodiments, D is in which G₂ is pyridinyl (for example pyridin-2-yl), piperidin-1-yl, 4,4-dimethylpiperidin-1-yl, 4,4-d¡fluoroper¡per¡per¡n-1 -yl, 2,6-dimethylpiperidin1 -yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (trifluoromethyl) piper¡n-1-yl, 4 -methylpiperidin-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, 3,3-dimethylazetidin-1-yl, or oxazolyl (for example, 1,3-oxazole- 2-yl) and D is optionally substituted with one or more R_M Additional which are selected from the group consisting of halogen (e.g. fluoro, chloro) and CiC alkyl₆ (for example, methyl).

In another embodiment of this aspect of the invention, D is p3

<img file="MX346264B_D0523.tif" />

N in which G! is N, CH, or CR_M; G₂ is, in which

<img file="MX346264B_D0524.tif" />

199

IMPI

MEXICAN INSTITUTE

BE LA PROPERTY industrial / °³

N '

i. is a monocyclic 4-8 membered nitrogenous heterocycle (e.g. azetidinyl, pyrrole idi ni lo, piperid ini lo) attached to the parent molecular moiety through a nitrogen atom and substituted with L4-G3 and optionally substituted with one or more R_G2; L₄ is a bond, Ci-C alkylene₆, -O-, or -S (O)₂-; G₃ is aryl (eg, phenyl), cycloalkyl (eg, cyclohexyl), or heterocycle (eg, thienyl) in which each G₃ is optionally substituted with one or more R_G3; Rg2 and Rg3 each time they appear are each independently halogen, -C (O) C ^ Ce alkyl, -C ^ Cg alkyl, -CrCg halogenoalkyl, -O-Ci-Cg alkyl, or -O -C ^ Cg halogenoalkyl; g is 0, 1, 2, or 3; and R_m is as defined above in relation to Formula l_AND. In a group of g₃or compounds according to this modality, D is aL ·, in which 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;

<img file="MX346264B_D0525.tif" />

and R_G3 are

IMPI

200 as defined above. In a further subgroup of

Rmi compounds of this modality, D is in which G₃ is phenyl optionally substituted with one or two R_G3; Rmi is each independently hydrogen, fluoro, chloro, or methyl; and R_G2 it is an optional substituent as described in the present application. In another group of compounds according to this modality, D, in which L₄ is alkylene of Ο, -Οθ, -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; yy R_G3 they are as defined above.

Even in another mode of this aspect of the

<img file="MX346264B_D0526.tif" />

201

<img file="MX346264B_D0527.tif" />

in which Gí is N, CH, or CR_M; G₂ is

IMPI

INSTITUTO MEXICANO BE LA NIOMEDAD INDUSTRIAL invention, D is * X-, in which&gt; v is a spiro bicyclic nitrogenous heterocycle, with bridging structure, or fused (for example, 3azabiciclo [3.2.0] hept-3-¡lo, 2-azabicyclo [2.2.2] oct-2-yl, 6azaspiro [2.5] oct-6-yl, octahydro-2H-isoindol-2-yl, 3azaspiro [5.5] undec-3-yl, 1,3-dihydro -2H-isoindol-2-yl, 1,4-dioxa-8azaspiro [4.5] dec-8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with L₄-G₃and one or more R_G2! L₄ is a bond, Cí-Ce alkylene, -O-, or -S (O)₂-; G₃ is aryl (eg, phenyl), cycloalkyl (eg, cyclohexyl), or heterocycle (eg, thienyl) in which each G₃is optionally substituted with one or more R_G3; Rg2 and Rg3 each occurrence are each independently halogen, -C (O) Cí-Ce alkyl, -Ci-C alkyl₆, -Cí-Ce halogenoalkyl, -O-Cí-Cb alkyl, or -O-Ci-C halogenoalkyl₆; g is 0, 1, 2, or 3;

and R_m is as defined above in relation to Formula l_AND.

In a group of compounds according to this embodiment, D is

<img file="MX346264B_D0528.tif" />

202

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY θ

J (Rm) or ^ vlv in which g is 0, 1, or 2; R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

<img file="MX346264B_D0529.tif" />

it is as defined above. In a further subgroup of compounds D is^RM1

<img file="MX346264B_D0530.tif" />

is each independently hydrogen, fluoro, chloro, or

<img file="MX346264B_D0531.tif" />

methyl, and is as defined above (e.g., 3-azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindole-2-lo, 220 azabicyclo [2.2.2] oct-2-yl, 6- azaspiro [2.5] oct-6-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isondol-2-yl, 1,4-dioxa-8-azaspiro [4.5] dec-8-yl).

Even in another mode of this aspect of the

203

<img file="MX346264B_D0532.tif" />

IMPI

MUUCANC INSTITUTE

Dt INDUSTRIAL RROM1TY

<img file="MX346264B_D0533.tif" />

monocyclic 4-8 membered nitrogenous (e.g. azetidinyl, pyrrolidinyl, pyperidinyl) substituted with one or more R_G2, in which R_G2each occurrence is each independently halogen, -C (O) Cí-Cg alkyl, -C-C alkyl₆ -C ^ Cg halogenoalkyl, -O-C ^ -Cg alkyl, or -O-C ^ Cg halogenoalkyl; and R_M is each independently halogen, -C ^ Cg alkyl, -Ci-Chaloalkyl₆, -O-Cí-Cg alkyl, or -O-C- | -C haloalkyl₆. In a group of compounds in accordance with this / ^&gt; Rg2

N modality, is azetidinyl, pyrrolidinyl, op¡pe rid in i substituted with one or two R_G2, in which R_G2 each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is each one way

<img file="MX346264B_D0534.tif" />

Rg2 independent fluoro, chloro, or methyl. For example it is 4,4-dimethylpiperidin-1-yl, 4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluorop Peridin-1-it_t 3,5 dimethylpiperidin-1 -yl, 4- (tr¡fluoromethyl) piperid¡n-1 -yl, 4-methylpiperidin Mexican IMPI wrrruTo

Bl LA HtOTUDAB

UNBUSTUAL

<img file="MX346264B_D0535.tif" />

204

1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, or 3,3-dimethylazetidin-1-yl.

For compounds of Formula l_AND

DL₃

The binding of X to the rest of the molecule can be conveniently represented by the abbreviated structural Formula X ', in which the groups bound to X maintain the same relative spatial orientation as drawn in Formula I._AND It is understood that in subsequent representations of the variable group X, the substituents of X will maintain the same relative positions and orientation as in Formula I._AND and Formula X '.

i ww

X '

Compounds of Formula l_AND include those in which the variable X is selected from the group consisting of X-1, X-2, X-3, and X-4 in which X-1, X-2, X-3, and X -4 maintain the same orientation as the structure X 'in relation to the rest of the molecule; in which the presence of = ^ = in X-1, X-2, and X-3 represents single or double bonds, Xt is Ci-C alkylene₂ or C alkenylene₂, X₂ and X₃ are each alkylene of Οτ-Ο₂ or

<img file="MX346264B_D0536.tif" />

In accordance with the above 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_TO:

ww ha

VJ

For

In certain embodiments, X is pyrrhoid in il or and is attached to the rest of the molecule as shown in Formula XB:

JVW \ ____ / X_BThe modalities in accordance with Formula X_B can exist in cis forms (X_Bi) or trans (X_B2):

WW% AAAf

<img file="MX346264B_D0537.tif" />

^XB1 Χθ2

Chiral carbon atoms in X_B, X_B1, and X_B2 they can have any of the absolute stereochemistry (R) or (S).

Even in another mode of this aspect of the

<img file="MX346264B_D0538.tif" />

206 invention, X is pyrrolyl and is attached to the rest of the molecule as

IMPI »E LA M» Nbda · INBUSTWIai shows in Formulas X_Cio X_C2:

<img file="MX346264B_D0539.tif" />

^XC1

<img file="MX346264B_D0540.tif" />

In certain embodiments, X is pyrrolidinyl and is attached to the rest of the molecule as shown in Formulas X_D1 or X_D2:

<img file="MX346264B_D0541.tif" />

^XD1 ^XD2

The modalities in accordance with Formulas X_D1 or X_D2 can exist in cis or trans forms and chiral carbon atoms in X_Di and X_D2 they can have any of the absolute stereochemistry (R) or (S). In certain embodiments, X is azetidinyl and is attached to the rest of the molecule as shown in Formulas X_E1 or X_E2:

<img file="MX346264B_D0542.tif" />

^XE1

<img file="MX346264B_D0543.tif" />

^XE2

Chiral carbon atoms in X_E1 and X_E2 independently they may have either absolute (R) or (S) stereochemistry.

In some preferred embodiments of this aspect of the invention, X is X_TO, Xb, Xbi, Xb2, Xci, or Xc2 and L-ι, L₂, and L₃ they are each

207

<img file="MX346264B_D0544.tif" />

a link. In some other modalities, X is^Y_Ci. ^AND~? ° X = 'V

IMPI

INSTITUTO MEXICANO Oí LA PROPERTY industrial

Li, L₂, and L₃ they are each a link. In another embodiment, X is X_E1 and Ls and L₂ are each methylene (i.e. -CH₂-), and L₃ is a link.

In the compounds of Formula l_AND, Y is -T'C (R₁R₂) N (R5) -TR_d and Z is -T'-C (R₈R₉) N (R₁₂) -TR_D; in which Τ ', Ri, R₂, Rs, Ra, Rg, R12, T, and Rd are as defined in the present application.

Preferably R_n R₂, R₅, R₈, R₉, and R₁₂ they are each independently hydrogen; Cn-Ce alkyl; or 3- to 6-membered carbocycle or heterocycle, in which each 3- to 6-membered carbocycle or heterocycle is independently optionally substituted each time it appears with one or more substituents selected from halogen or Ci-Ce alkyl ; in which R₂ and R₅, taken together with the atoms to which they are attached, optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R_TO, and R₉ and R₁₂ Taken together with the atoms to which they are attached, they optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R_TO in which R_TO it is as defined in the present application.

In certain embodiments of this aspect of the invention, R1 is hydrogen and R₂ and R₅, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (for

IMPI oewrOTOMUNCANo

D «THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0545.tif" />

208

<img file="MX346264B_D0546.tif" />

Item

<img file="MX346264B_D0547.tif" />

substituted with 0, 1, 2, 3, or 4 R_TO in which R_TO is halogen (eg fluoro, chloro); cyano; L_S-R_AND in which L_s is a single link and R_AND is Ci-Cg alkyl (e.g. methyl, ethyl),

-O-C-C alkyl₆ (e.g. methoxy), or -O-halogenoalkyl of

Ci-Ce (eg, trifluoromethoxy); or L_S-R_AND in which L_s is a double bond and R_AND is = C (R_SR_S') (for example,

CH₃ )·

In a preferred embodiment R₂ and R₅, taken together with the atoms to which they are attached form a pyrrolidine ring (that is,

<img file="MX346264B_D0548.tif" />

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

<img file="MX346264B_D0549.tif" />

In some other forms of this aspect of the

<img file="MX346264B_D0550.tif" />

209 invention, R₈ is hydrogen and R₉ and R₁₂ , taken together with the atoms

IMPI 'ΝΠΤΓυΤο MEXICANO DS LA PROPERTY INDUSTRIA !.

to which they are attached form a heterocycle of 3 to 12

<img file="MX346264B_D0551.tif" />

<img file="MX346264B_D0552.tif" />

<img file="MX346264B_D0553.tif" />

<img file="MX346264B_D0554.tif" />

is halogen (eg fluoro, chloro); cyano; L_s-Re in which L_s is a single link and R_and is C - C alkyl₆ (eg, methyl, ethyl), -O-C ^ Ce alkyl (eg, methoxy), or -O-C-C haloalkyl₆ (eg, trifluoromethoxy); or L_S-R_AND in which L_s is a double bond and R_AND is = C (R_sRs') (for example,,). In

H CH₃ a preferred embodiment, R₉ and R₁₂, taken together with the atoms to which they are attached form a pyrrolidine ring (that is,

<img file="MX346264B_D0555.tif" />

methyl, ethyl, or cyano.

R_to in which R_TO is fluoro, methoxy,

In another preferred embodiment R₉ and R₁₂, take two

210

<img file="MX346264B_D0556.tif" />

together with the atoms to which they are attached form a ring

IMPI

MUICANO INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0557.tif" />

As used in the present application, a chral carbon in any rings that are formed by joining R₂ and R₅ or R₉ Y

R₁₂ it can possess either (R) or (S) stereochemistry. A pyrrolidine ring (is

<img file="MX346264B_D0558.tif" />

) formed from either

R₂ and R₅ or

R₉ and R₁₂ preferably has the (S) stereochemistry (that is,

V ¹).

In this aspect of the invention, T 'is independently selected each time it appears from a bond, -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 each time it appears with one or more R_TO, and Ra and Rb are as described in the present application. In particular, in cases where T 'is -C (O) N (R_b) -, R_bit can be hydrogen (ie T 'is -C (O) N (H) -). In certain embodiments, T 'is imidazolyl (i.e.

<img file="MX346264B_D0559.tif" />

H

N

<img file="MX346264B_D0560.tif" />

211

<img file="MX346264B_D0561.tif" />

optionally substituted each time it appears with one or more R_TO in

IMPI

INSTITUTO MEXICANO DE LA EROPICDAD INDUSTRIAL which R_TO is halogen (e.g. fluoro, chloro), C alkyl_rC₆ (e.g., methyl, ethyl), or Ci-C haloalkyl₆ (eg, trifluoromethyl). In some embodiments, T 'is imidazolyl (i.e.

<img file="MX346264B_D0562.tif" />

This aspect of the invention contemplates particular combinations of A with Y and B with Z. Non-limiting examples of Y preferred when A is carbocycle of C₅-C₆ (eg phenyl) or 5-6 membered heterocycle (eg pyridinyl or thiazolyl) and Z preferred when B is carbocycle of C₅-C₆ (eg, phenyl) or 5-6 membered heterocycle (eg, pyridinyl or thiazolyl) include:

<img file="MX346264B_D0563.tif" />

<img file="MX346264B_D0564.tif" />

<img file="MX346264B_D0565.tif" />

<img file="MX346264B_D0566.tif" />

HO.

<img file="MX346264B_D0567.tif" />

<img file="MX346264B_D0568.tif" />

<img file="MX346264B_D0569.tif" />

<img file="MX346264B_D0570.tif" />

<img file="MX346264B_D0571.tif" />

<img file="MX346264B_D0572.tif" />

<img file="MX346264B_D0573.tif" />

<img file="MX346264B_D0574.tif" />

212

<img file="MX346264B_D0575.tif" />

<img file="MX346264B_D0576.tif" />

<img file="MX346264B_D0577.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY .

<img file="MX346264B_D0578.tif" />

I HN ^Rd '^T

<img file="MX346264B_D0579.tif" />

<img file="MX346264B_D0580.tif" />

<img file="MX346264B_D0581.tif" />

<img file="MX346264B_D0582.tif" />

in which T and R_D they are as defined in the present application.

In certain embodiments of this aspect of the invention, A

<img file="MX346264B_D0583.tif" />

optionally substituted with one or more R_TO as described in the present application, or YA is

<img file="MX346264B_D0584.tif" />

Non-limiting examples of preferred Y, in which T 'is a bond, include:

<img file="MX346264B_D0585.tif" />

<img file="MX346264B_D0586.tif" />

<img file="MX346264B_D0587.tif" />

<img file="MX346264B_D0588.tif" />

<img file="MX346264B_D0589.tif" />

L- LM

213

<img file="MX346264B_D0590.tif" />

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX346264B_D0591.tif" />

in which T and R_D they are as defined in the present application.

In certain embodiments of this aspect of the invention, B

<img file="MX346264B_D0592.tif" />

as described in the present application, or BZ is

<img file="MX346264B_D0593.tif" />

Non-limiting examples of preferred Z, in which T is a bond, include:

<img file="MX346264B_D0594.tif" />

<img file="MX346264B_D0595.tif" />

<img file="MX346264B_D0596.tif" />

<img file="MX346264B_D0597.tif" />

<img file="MX346264B_D0598.tif" />

<img file="MX346264B_D0599.tif" />

in which T and R_D they are as defined in the present application.

T each time it appears is independently a bond or -C (O) -L_S'-, in which L_s'is as defined in the present

<img file="MX346264B_D0600.tif" />

214

<img file="MX346264B_D0601.tif" />

IMPI

INSTITUTO MEXICANO Bt LA PROPERTY INDUSTRIAL application. L_s'includes, but is not limited to,

<img file="MX346264B_D0602.tif" />

, in which L_s'is optionally substituted with one or more R_L; and R_l is a substituent such as, but not limited to, carbocycle (eg, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, or heterocycle (eg, tetrahydrofuranyl, tetrahydropyranyl).

R_d is hydrogen or R_TO in which R_TO it is as defined in the present application. Therefore R_D includes, but is not limited to, R_to in which R_TO is L_s-Re, and L_s and R_and they are as defined in the present application. Therefore R_d includes, but is not limited to, Ls-Re in which L_s is a link and R_and is -N (R_sRs'), -N (R_S) C (O) R_S', -N (R_s) C (O) N (Rs'Rs ”), -N (R_s)SW₂R_s', -N (R_s)SW₂N (R_s'Rs ”), -N (R_s) S (O) N (R_s'Rs ”), -N (R_S) C (O) OR_S', or -N (R_s) S (O) -R_s'; or carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, cyano, C-Ce alkyl, C-alkenyl₂-C₆, C alkynyl₂-C₆, or haloalkyl of CrCe.

In one embodiment of this aspect of the invention, R_D is Ls-Re in which L_s is a link and R_AND is -N (Rs) C (O) OR_s'or

IMPI

INSTITUTE Μ21ΚΛΝΟ of the currency

Industrial

<img file="MX346264B_D0603.tif" />

215 3-12 membered heterocycle (eg, pTTrUTIÜ111a, prprtdin, azepanil) in which R_s and Rs' are as defined in the present application. For example R_D is preferably L_s-Re in which L_s is a bond and Re is -N (H) C (O) OMe.

Therefore in accordance with the description above T-

<img file="MX346264B_D0604.tif" />

<img file="MX346264B_D0605.tif" />

TR_D it can also include particular stereochemical configurations; therefore TR_D includes, but is not limited to:

216

<img file="MX346264B_D0606.tif" />

Λ / WII ^{1 1}

<img file="MX346264B_D0607.tif" />

<img file="MX346264B_D0608.tif" />

<img file="MX346264B_D0609.tif" />

etc.

In accordance with this aspect of the invention, non-limiting examples of Y preferred when A is carbocycle of C_s-C₆ (eg, phenyl) or 5-6 membered heterocycle (eg, pyridinyl or thiazolyl) and Z preferred when B is C5-C carbocycle₆ (eg, phenyl) or 5-6 membered heterocycle (eg, pyridinyl or thiazolyl) include:

<img file="MX346264B_D0610.tif" />

<img file="MX346264B_D0611.tif" />

217

<img file="MX346264B_D0612.tif" />

<img file="MX346264B_D0613.tif" />

<img file="MX346264B_D0614.tif" />

<img file="MX346264B_D0615.tif" />

Non-limiting examples of

And preferred when A is

<img file="MX346264B_D0616.tif" />

optionally substituted with one or more R_TO as

<img file="MX346264B_D0617.tif" />

was described in the present application, and YA is

<img file="MX346264B_D0618.tif" />

IMPI wentiruit »m« ucano

ΗΜΜΟΗΜΑΟ

INDUSTRY*.

<img file="MX346264B_D0619.tif" />

218

<img file="MX346264B_D0620.tif" />

<img file="MX346264B_D0621.tif" />

<img file="MX346264B_D0622.tif" />

<img file="MX346264B_D0623.tif" />

we

<img file="MX346264B_D0624.tif" />

Non-limiting examples of preferred Z in which B

<img file="MX346264B_D0625.tif" />

optionally substituted with one or more R_TO as described in the present application, and BZ is

<img file="MX346264B_D0626.tif" />

include:

IMPI '^ ITf.MWfCANo ° * «omedad

INDUSTRIAL

<img file="MX346264B_D0627.tif" />

219

<img file="MX346264B_D0628.tif" />

<img file="MX346264B_D0629.tif" />

<img file="MX346264B_D0630.tif" />

<img file="MX346264B_D0631.tif" />

220

In yet another aspect, the present invention includes compounds of Formula I._F and pharmaceutically acceptable salts thereof:

D

A- -X- B.

Y 'Z lp in which:

IMPI

INSTITUTE WX1CANO

DI THE INDUSTRIAL PROPERTY

X is

<img file="MX346264B_D0632.tif" />

<img file="MX346264B_D0633.tif" />

in which X is optionally substituted with one or more R_TO

<img file="MX346264B_D0634.tif" />

in which A is optionally substituted with one or more R_TO;

<img file="MX346264B_D0635.tif" />

optionally substituted with one or more of R_TO; Y

Y, Z, R_to, and D are as described in the present application above (e.g., Y, Z, R_TO, and D as described for Formula I, l_TO, l_B, you. Go, or I_and, preferably as described for Formula I_AND).

In one embodiment of this aspect of the invention, X is

<img file="MX346264B_D0636.tif" />

221

<img file="MX346264B_D0637.tif" />

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0638.tif" />

in which A is optionally substituted with one or more R_TO; B is

<img file="MX346264B_D0639.tif" />

in which B is optionally substituted with one or more R_TO; And it is

<img file="MX346264B_D0640.tif" />

<img file="MX346264B_D0641.tif" />

<img file="MX346264B_D0642.tif" />

Rd

<img file="MX346264B_D0643.tif" />

<img file="MX346264B_D0644.tif" />

<img file="MX346264B_D0645.tif" />

<img file="MX346264B_D0646.tif" />

<img file="MX346264B_D0647.tif" />

<img file="MX346264B_D0648.tif" />

<img file="MX346264B_D0649.tif" />

<img file="MX346264B_D0650.tif" />

<img file="MX346264B_D0651.tif" />

<img file="MX346264B_D0652.tif" />

222

IMPI

MEXICAN INJTTTITO

DE LA FROHEOAD INDUSTRIAL y D, R_to, T and R_d are as defined previously in the present application (e.g., as described for Formula I, l_TO, l_B, l_c, Id or Ie, preferably as described for Formula I_AND).

In another embodiment in accordance with this aspect of the invention, A or B are optionally substituted with one or more substituents selected from: R_TO in which R_TO is each independently halogen (eg, fluoro, chloro); L_s-R_and in which L_s is a single link, and R_AND is -C ^ -Ce alkyl (e.g. methyl), -OR_s (for example, -O-C_rC_and, -OCH₃), or -C-C alkyl₅ optionally substituted with one or more halogen (e.g., -CF₃); or L_s-Re in which L_s is a Ci-C alkylene₆ and R_and is -OR_s (e.g., -alkyKCf-CebO-CpCe alkyl, -CH₂OCH₃). This embodiment includes compounds in which both A and B are substituted with an R_TO; compounds in which both A and B are substituted with zero R_TO; compounds in which A is substituted with an R_TO and B is substituted with zero R_TO; and compounds in which A is substituted with zero R_TO and B is replaced with an R_TO.

Preferably, A is

<img file="MX346264B_D0653.tif" />

<img file="MX346264B_D0654.tif" />

<img file="MX346264B_D0655.tif" />

In a further embodiment of this aspect of the invention, TR_D is independently selected each time it appears from the group consisting of

<img file="MX346264B_D0656.tif" />

<img file="MX346264B_D0657.tif" />

<img file="MX346264B_D0658.tif" />

<img file="MX346264B_D0659.tif" />

IMPI iNrrnvr · Mexican miamohedad iNovmuAL

224

<img file="MX346264B_D0660.tif" />

in which compounds having the (S) stereochemistry (e.g.,

<img file="MX346264B_D0661.tif" />

) and in which D is as defined hereinbefore.

In another embodiment, this aspect of the invention features a compound of Formula I._F and pharmaceutically acceptable salts thereof, in which:

<img file="MX346264B_D0662.tif" />

<img file="MX346264B_D0663.tif" />

which A is optionally substituted with one or more R_TO; B is

<img file="MX346264B_D0664.tif" />

more R_to; And it is

<img file="MX346264B_D0665.tif" />

IMPI meMcano institute

OF THE PROPERTY

<img file="MX346264B_D0666.tif" />

<img file="MX346264B_D0667.tif" />

<img file="MX346264B_D0668.tif" />

<img file="MX346264B_D0669.tif" />

<img file="MX346264B_D0670.tif" />

<img file="MX346264B_D0671.tif" />

<img file="MX346264B_D0672.tif" />

R_d they are as defined in the present application above. A particular subgroup under this modality includes

<img file="MX346264B_D0673.tif" />

<img file="MX346264B_D0674.tif" />

226

IMPI

INSTITUTO MMKMto Ml ^ FRQMEDA · INBUST »! *)

<img file="MX346264B_D0675.tif" />

<img file="MX346264B_D0676.tif" />

<img file="MX346264B_D0677.tif" />

; and D is as defined in the present application above.

In yet another embodiment, this aspect of the invention features compounds of Formula I._F and pharmaceutically acceptable salts thereof, in which: X is

<img file="MX346264B_D0678.tif" />

each independently

<img file="MX346264B_D0679.tif" />

<img file="MX346264B_D0680.tif" />

D, R_to, T and R_d they are as defined in the present application above. A particular subgroup under this modality includes compounds in which TR_D each is independently selected from

<img file="MX346264B_D0681.tif" />

<img file="MX346264B_D0682.tif" />

apply earlier.

In accordance with each of the above embodiments and description of this aspect of the invention of Formula I_Fare groups and subgroups of compounds that have particular values ​​for D. There are groups and subgroups of compounds included in each of the previous modalities with the

<img file="MX346264B_D0683.tif" />

IMPI umnyro mAicano MlAPtOflIDAP INDUSTRIAL

228 following particular values ​​for D:

In some groups of compounds in accordance with the

Formula l_F and the above embodiments and description of this aspect of the invention, D is

<img file="MX346264B_D0684.tif" />

, in which R_M is fluoro, chloro, tert-butyl, -O-CH₂CH₃, -O-CF₃, -O-CH₂CHF_2&gt; -O-CH₂CH₂OCH₃, -OCH₂- (3-ethyloxetan-3-yl), -O-CH₂- (1,3-dioxolan-4-yl), -O-cyclopentyl, -0-cyclohexyl, -O-phenyl, -O- (1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, -SO₂Me, or -N (t-Bu) C (O) Me and D is optionally substituted with one or more R_M additional, which are selected from the group consisting of halogen (e.g., fluoro, chloro) or C-alkyl_rC₆ (for example, methyl).

In other groups of compounds according to Formula I_F and the above description and modalities of this g₂ or

aspect of the invention, D is in which G₂ is pyridinyl (for example, pyridin-2-yl), piperidin-1-yl, 4,4-d¡met¡lp¡per¡per¡din-1-yl, 4.4d ifluo ropiperidi n-1 -i lo, 2 , 6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-l-yl, 4 (trifluoromethyl) piperidin- 1 -yl, 4-methylper¡per¡n-1-yl, 4-tertbutylpiperidin-1-yl, 2-oxop¡per¡d¡n-1-¡lo, 3,3-d¡met Lazetid¡n-1-ylo, u ²²⁹ IMPIAS

UUiia &lt;/ Τ · Μ * ΙϋΛΝο • E LA nOMtCMD tA- ~¹ industrial oxazolyl (e.g. 1,3-oxazol-2-yl) and D is optionally substituted with one or more R_M Additional which are selected from the group consisting of halogen (eg, fluoro, chloro), or Ci-Cg alkyl (eg, methyl). In particular there are compounds according to these groups in which D is g₂ ; G₂ is piperidin-1 -yl, 4,4-dimethylpiperidin-1 -yl, 4,4di-fluoropiperidin-1-yl, 2,6-d-imethylpiperidi n-1 -yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4- (tr¡fluoromethyl) piperidin-1-yl, 4-methylpiper¡per¡n-1 -yl, 4-tert-but¡lp¡perid¡n-1¡lo, 2-oxopiperid¡n-1-yl, or 3,3-d¡meth¡lazet¡din-1-yl; and R_M1 is each independently hydrogen, fluoro, chloro, or methyl.

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

<img file="MX346264B_D0685.tif" />

is N, CH

<img file="MX346264B_D0686.tif" />

CR_M; G₂ is, in which'X-, R_M, and g are as defined in the present application above. In particular in accordance

230

<img file="MX346264B_D0687.tif" />

with these groups, R_M is each independently fluoro,

IMPI

MEXICAN INSTITUTE

FROM THE INDUSTRIAL RRONEDAP chlorine, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2;

<img file="MX346264B_D0688.tif" />

it is as defined above.

In additional subgroups ^G3

<img file="MX346264B_D0689.tif" />

L₄ is a link; G₂ is ; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or ^G3

<img file="MX346264B_D0690.tif" />

trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups, 'Th · is 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperidin-1-yl, 4-phenylpiperidin-1 -yl, 4-phenyl-I-3,6-dihydropyridin-1 (2H) -yl, 4,4-diphenyl-piperidin-1-yl, 4-acetyl-4-phenylpiperidin-1-yl, 4- (4-methoxyphenyl ) piperidin-1-yl, 4- (4-fluorophenyl) piperidin-1-yl, or 3-phenylpiperidin-1-yl; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In other subgroups L₄ is Ci-C alkylene₆, -O-, or -S (O)₂-; G₂ is

<img file="MX346264B_D0691.tif" />

231

IMPI

INSTITUTO MEXICANO M LA MONEDAD INDUSTRIAL

<img file="MX346264B_D0692.tif" />

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

G₃^l4 6 N ^Yparticular subgroups, is 4-tosylpiperazin-1 -yl, 4-phenoxypiperidin-1-yl, 3-phenoxypyrrol¡d¡n-1-¡lo, 4-benc¡lp¡per¡d¡n-1 -yl, 4-phenethylpiperidin-1-yl, or 3-phenylpropyl) piperidin-1-yl; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In subgroups of compounds

<img file="MX346264B_D0693.tif" />

<img file="MX346264B_D0694.tif" />

additional D is ^ vLv, in which 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

<img file="MX346264B_D0695.tif" />

trifluoromethoxy and X- and R_G3 they are as defined above.

In other groups of compounds

D is

IMPI

Mexican INSTITUTE

OF THE CURRENCY

INDUSTRIAL

<img file="MX346264B_D0696.tif" />

232

<img file="MX346264B_D0697.tif" />

, in which L₄ is C ^ Cg 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,

N ............... . methoxy, trifluoromethyl, or trifluoromethoxy; yy R_G3 they are as defined above. In additional compound subgroups D^G3

I ^RG2 is uvL in which G₃ is phenyl optionally substituted with one or two R_G3 as defined in the present application above; R_M1 is each independently hydrogen, fluoro, chloro, or methyl; and R_G2 is an optional substituent, as described above, which is selected from the group consisting of -C (O) -Ci-C alkyl₆, -Ci-Cg alkyl, -C ^ Cg halogenoalkyl, -O-C ^ Cg alkyl, and -O-Ci-C halogenoalkyl₆.

In other groups of compounds in accordance with the

<img file="MX346264B_D0698.tif" />

233

IMPI

INSTITUTO MEXICANO Df LA MONEDAD industrial

Formula l_F and the above embodiments and description of this aspect of the invention, D is

<img file="MX346264B_D0699.tif" />

which G₄ is N, CH, or

CR_M; G₂ is r *, in which, R_M, and g are as defined above in the present application. In particular according to these subgroups, R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; g is 0,

1 or 2; y is 3-azabicyclo [3.2.0] hept-3-yl, 2-azabicyclo [2.2.2] oct2-ilo, 6-azaspiro [2.5] oct-6-yl, octahydro-2H-isoindol-2 -Ilo, 3azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-yl, or 1,4-dioxa8-azaspiro [4.5] dec-8-yl. In additional subgroups of compounds

Ί (Rm) s

D is X in which g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or. ... X ........ _ trifluoromethoxy; and / H · is as defined above. In

IMPI imuruTO Mexican

OF THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0700.tif" />

234

<img file="MX346264B_D0701.tif" />

R_M1

R_Mone additional subgroups of compounds D is in which

R_M1 is each independently hydrogen, fluoro, chloro, or

<img file="MX346264B_D0702.tif" />

methyl and / H. is as defined above (for example, 3-azabicyclo [3.2.0] hept-3-¡lo, octahydro-2H-¡soindole-2-¡lo, 2azabicyclo [2.2.2] oct-2-yl, 6-azaspiro [ 2.5] oct-6-yl, 3azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, 1,4-dioxa-8azaspiro [4.5] dec-8-yl ).

In other groups of compounds according to Formula I_F and the above modalities and description of this

<img file="MX346264B_D0703.tif" />

Rm aspect of the invention, D is a nitrogen-containing 4-8 membered monocyclic heterocycle (eg, azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R_G2. in which R_G2 each occurrence is each independently halogen, -C (O) Ci-C alkyl₆, -alkyl of

235 IMPI ^^ &lt;”srnyromexicano

DÍ LA ΜΙΟΜΕΝΑΓ Y7— * ^ W ~

INDUSTW! λ&gt;

Ci-C₆, -Ci-C halogenoalkyl₆, -O-Ci-C alkyl₆, or

-O-Ci-C halogenoalkyl₆; and R_M is each independently halogen, -CrCs alkyl, -C-Chaloalkyl₅, -O-CpCe alkyl, or -O-C ^ Cg haloalkyl. In each group of compounds in accordance with the previous modalities

<img file="MX346264B_D0704.tif" />

is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R_G2, in which R_G2 each occurrence is each methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is each independently fluoro, chloro, or methyl. By

Z ^&gt; Rg2 N example is 4,4-dimethylpiperidin-1 -yl, 4,4-difluoropiperidin-1-yl, 2,6-dimethylpiperidin-1-lo, 4- (propan-2-yl ) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4 (trifluoromethyl&gt; piperidin-1-yl, 4-methylpiperidin-1-yl, 4-tertbutylpiperidin -1 -yl, 2-oxopiperidin-1-yl, or 3,3-dimetilazetidin-1-yl.

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

<img file="MX346264B_D0705.tif" />

236

<img file="MX346264B_D0706.tif" />

in which:

X is

<img file="MX346264B_D0707.tif" />

is optionally substituted with one or more R_TO

<img file="MX346264B_D0708.tif" />

in which A is optionally substituted with one or more R_TO;

<img file="MX346264B_D0709.tif" />

, in the

IMPI

INSTHVT · MEXICAN

OF INDUSTRIAL PROPERTY, in which X which B is optionally substituted with one or more R_TO;

Y, Z, R_to, and D are as previously described in the present application (for example, as described for Formula I, l_TO, l_B, le, Id, Ie or I_F, preferably as described for Formula I_AND).

In one embodiment, this aspect of the invention features compounds of Formula I._G and pharmaceutically acceptable salts

<img file="MX346264B_D0710.tif" />

thereof, in which: X is

A is

<img file="MX346264B_D0711.tif" />

, in which A is optionally

<img file="MX346264B_D0712.tif" />

IMPI iMsmuiv Mexican

Dt THE NORITY

INDUSTRIAL

237 replaced with an R_TO; B is

<img file="MX346264B_D0713.tif" />

in which B is optionally substituted with an R_TO; R_TO is halogen (eg fluoro, chloro); L_s-Re in which L_s is a single link and R_AND is -alkyl of ΰ_ΓΟ₆ (for example, methyl), -OR_s (eg, -O-alkyl of

C ^ Ce, -OCH3), or -Ci-C alkyl₆ optionally substituted with one or more halogens (e.g. -CF₃); or L_S-R_AND in which L_s is an alkylene of C ^ Ce and Re is -OR_s (e.g., -alkylCi-Cej-O-alkyl of

C_rC_5l -CH₂OCH₃); Y and Z are each independently

<img file="MX346264B_D0714.tif" />

<img file="MX346264B_D0715.tif" />

TR_d is each independently

<img file="MX346264B_D0716.tif" />

238

IMPI

MEXICAN INSTITUTE

OF THE industrial FROFTETY

<img file="MX346264B_D0717.tif" />

apply earlier.

In another embodiment, this aspect of the invention features compounds of Formula I._G and pharmaceutically acceptable salts thereof, in which X is

<img file="MX346264B_D0718.tif" />

in which A is optionally substituted with an R_TO; B is

<img file="MX346264B_D0719.tif" />

, in which B is optionally substituted with an R_TO;

R_to is halogen (eg fluoro, chloro); L_s-Re in which L_s is a single link and R_AND is -C-C alkyl_AND (for example, m linden), -OR_s(e.g. mplo, -O-Ct-C alkyl₆, -OCH₃), or -Ci-C alkyl₆

239

<img file="MX346264B_D0720.tif" />

optionally substituted with one or more halogens (e.g.

IMPI

INSTTTUT · MUBCANO

M LA PMHtBAD iNnusTBiAt

-CF₃); or Ls-Re in which L_s is a Ci-C alkylene₆ and Re is -OR_s (e.g. -Cj-Csj-O-Cj-Alkyl-Ce, -CH₂OCH₃); Y and Z are each independently

<img file="MX346264B_D0721.tif" />

compounds having the (S) stereochemistry

<img file="MX346264B_D0722.tif" />

IMPI «NSTITUTO MEX1CAN 'MtAfMMEDAD

INDUSTRY!

240 'Me ⁰ (for example, θ); and D is as defined above in the present application. This subgroup includes compounds in which A and B are both substituted with an R_TO; compounds in which A and B are both substituted with zero R_to; compounds in which A is substituted with an R_TO and B is substituted with zero R_to; and compounds in which A is substituted with zero R_TO and B is replaced with an R_TO. In particular, this subgroup includes compounds in which A is

<img file="MX346264B_D0723.tif" />

<img file="MX346264B_D0724.tif" />

<img file="MX346264B_D0725.tif" />

In accordance with each of the above embodiments and description of this aspect of the invention of Formula I_G are the groups and subgroups of compounds that have particular values ​​for D. In each of the above modalities, groups and subgroups of compounds with the following particular values ​​for D are included:

241

<img file="MX346264B_D0726.tif" />

IMPI

MEXICAN INSTITUTE

M THE «OF1EDAU INeuSTRIAl

Groups of compounds in accordance with this aspect of the invention include compounds in which D is aryl of C₆-C₁₀ (eg, phenyl, naphthyl, indanyl), or 5 to 10 membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo [d] thiazolyl, benzo [d] thiazolyl, indazolyl, benzo [d] [ 1,3] dioxol-5-yl), and D is substituted with one or more R_M. Particular subgroups in accordance with this aspect and these modalities include compounds in which R_M is halogen (eg fluoro, chloro, bromo); Cf-Cg alkyl (eg, tert-butyl); C, -C alkyl_ssubstituted with one or more halogens (e.g. CF₃); -O-CfCg alkyl (for example, -O-CH₂CH₃); -O-Ci-C alkyl₆ substituted each time it appears with one or more halogens (e.g., -O-CF₃, -O-CH₂CHF₂) u -O-Ci-C alkyl₆ (-O-CH₂CH₂OCH₃); -O-C-C alkyl₆ (for example, -O-CH₂) substituted with an optionally substituted 3- to 12-membered heterocycle (eg, 3-ethyloxetan-3-yl, 1,3-dioxolan-4-yl); -OR_s in which R_s is an optionally substituted 3- to 12-membered carbocycle or heterocycle (eg, cyclopentyl, cyclohexyl, phenyl, 1,3-dioxan-5-yl); -N (R_S) C (O) R_S'in which R_s and Rs' are each independently C alkyl_rC_AND(eg, -N (t-Bu) C (O) Me); SF₅; -SW₂R_s in which R_s is Ci-C alkyl₆ (for example, -SO₂I); or carbocycle of C₃-C₁₂ (eg cyclopropyl, cyclohexyl, phenyl). Other subgroups under this embodiment include compounds in which D is phenyl substituted with G₂ and optionally substituted with one or more R_M, in which G₂ is a 3- to 12-membered heterocycle (e.g. pyridinyl,

242 IMPI ^

IMSimn MEXICAN. DE LA FRONÉDAD J industbiai pi pe ridini I o, pyrrolidinyl, azetidinyl, oxazolyl) in which the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, cyano, Cy-Ce alkyl ( e.g. methyl), C alkenyl₂-C₆, C alkynyl₂-C₆, C-Ce haloalkyl (for example, CF₃), C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -O-Ci-C alkyl₆ (for example, -O-CH₃), -C (O) ORs (for example, -C (O) OCH₃), -C (O) R_S (for example, -C (O) CH₃), -N (R_sRs'), or L₄-G₃R_M is halogen (eg fluoro, chloro), alkyl (eg methyl), haloalkyl (eg CF₃), or -O-alkyl of Ο ^ Οβ (for example, -O-CH₃); and L₄, G₃, R_s, and Rs' are as defined above in the present application.

In some groups of compounds according to Formula I_G and the above modalities and description of this

Rm aspect of the invention, D is, in which R_M is fluoro, chloro, tert-butyl, -O-CH₂CH₃, -O-CF₃, -O-CH₂CHF₂, -O-CH₂CH₂OCH₃, -OCH₂- (3-ethyloxetan-3-yl), -O-CH₂- (1,3-dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -O- (1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, -SO₂Me, or -N (t-Bu) C (O) Me and D is optionally substituted with one or more R_M Additional, which are selected from the group consisting of halogen (eg, fluoro, chloro) or Ci-Ce alkyl (eg, methyl).

IMPI UWNTUTOMJUUCAW · WMfMmMD ΙΝΙΧιΛλλ!

In other groups of compounds in accordance with the

Formula l_G and the above modes and description of this g₂ aspect of the invention, D is, in which G₂ is pyridinyl (eg pyridin-2-yl), piperidin-1 -yl, 4,4-d¡methylp¡perid¡n-1 -yl, 4,4difluoropiperidin-1-yl, 2,6-dimethylp ¡Peridin-1-yl, 4- (propan-2-yl) piperidin-1-yl, 4-fluoropiperidin-1-yl, 3,5-dimethylpiperidin-1-yl, 4 (trifluoromethyl) piper¡n-1 - yl, 4-methylpiperidin-1-yl, 4-ter

<img file="MX346264B_D0727.tif" />

butylpiperidin-1-yl, 2-oxopiperidin-1-yl, 3,3-dimethylazetidin-1-yl, or oxazolyl (eg, 1,3-oxazol-2-yl) and D is optionally substituted with one or more R_M Additional which are selected from the group consisting of halogen (e.g., fluoro, chloro), or Ci-C alkyl₆ (for example, methyl). In particular according to these groups there are compounds in which D is g₂ rJw; G₂ is piperidin-1-yl, 4,4-dimethylpiper¡d¡n-1-¡lo, 4,4difluoropiperidin-1-yl, 2,6-dimethylpiper¡d¡n-1-yl, 4- (propan -2¡l) piperid¡n-1-yl, 4-fluoropiperidin-1-yl, 3,5-d¡methylpiperidin-1-yl, 4 (trifluoromethyl) piperidin-1-yl, 4-methylpiperidi n-1-yl, 4-tert-butylpiperidin-1-yl, 2-oxopiperidin-1-yl, or 3,3-dimethylazetidin-1-yl; and R_M1 is each independently hydro, fluoro, chloro, or

IMPI lltJTTHJTO MEXKANO

M THE MteriEBAD

INDUSTRIAL

<img file="MX346264B_D0728.tif" />

244

In other groups of compounds in accordance with methyl.

Formula l_G and the above embodiments and description of this aspect of the invention, D is

<img file="MX346264B_D0729.tif" />

<img file="MX346264B_D0730.tif" />

CR_m; G₂ is X., in which X ·, R_M, and g are as defined above in the present application. In particular in accordance with these groups, R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; g is 0, 1, or 2;

<img file="MX346264B_D0731.tif" />

it is as defined above in the present application.

In additional groups L₄ is a link; G₂ is

<img file="MX346264B_D0732.tif" />

R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups,

IMPI Mexican nwnvro of the former tNDUSTIUAL htoad

<img file="MX346264B_D0733.tif" />

245

<img file="MX346264B_D0734.tif" />

is 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-1-yl, 4-phenylpiperazin

1-¡lo, 4-phenylpiperid¡n-1 -yl, 4-phenyl-3,6-d¡h¡drop¡rid¡n-1 (2H) -yl, 4,4-diphenylpiperidin-1-yl, 4- acetyl-4-phenylpiper¡din-1 -yl, 4- (4-methoxyphenyl) piper¡d¡n-1-yl, 4- (4-fluorophenyl) piper¡d¡n-1-¡lo, or 3-phenylpiperidin- 1-yl; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or

2. In other subgroups L₄ is C alkylene_rC₆, -O-, or -S (O)₂-; G₂ is

<img file="MX346264B_D0735.tif" />

; R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In

<img file="MX346264B_D0736.tif" />

particular subgroups, is 4-tosylpiperazin-1-yl, 4-phenoxy piperidin-1-yl, 3-phenoxypyrrolidin-1-yl, 4-benzylpiperidin-1-yl, 4-phenethylpiperidin-1-yl, or 3-phenylpropyl) piperidin-1-yl; R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In additional subgroups of

<img file="MX346264B_D0737.tif" />

246

<img file="MX346264B_D0738.tif" />

compounds D is

G₃ ¡ (^RM&gt; g

IMPI

INSTITUTO MEXICAN DE LA PROPERTY INDUSTRIAL in which 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

<img file="MX346264B_D0739.tif" />

trifluoromethoxy; y% y R_G3 they are as defined above.

<img file="MX346264B_D0740.tif" />

[| 4- (R_M)₈

In other groups of compounds D is * / WVi, in which L₄ is Ci-C alkylene₆, -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

<img file="MX346264B_D0741.tif" />

they are as defined above.

IMPI

MIXICAN INSTITUTE

FROM ΙΛ TROMBDA »inbustriau

<img file="MX346264B_D0742.tif" />

247

In additional subgroups of compounds D is

Rmix.

<img file="MX346264B_D0743.tif" />

G₃ is phenyl optionally substituted with one or two R_G3 as defined above in the present application; R_Mi is each independently hydrogen, fluoro, chloro, or methyl; and R_G2 is an optional substituent, as described above, which is selected from the group consisting of -C (O) Cj-Ce alkyl,

-Ci-C alkyl_s, -Ci-Ce halogenoalkyl, -O-Ci-C alkyl₆, and

-O-halogenoalkyl of Οτ-Οβ.

In other groups of compounds in accordance with the

Formula l_G and the above embodiments and description of this aspect of the invention, D is

<img file="MX346264B_D0744.tif" />

in which Gt is N, CH

<img file="MX346264B_D0745.tif" />

Rm, and g are as defined previously in the present application. In particular according to these subgroups, R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; g is 0,

IMPI

WnWOMUKAMO

D £ THE PROPERTY

INDUSTMAl

<img file="MX346264B_D0746.tif" />

248

<img file="MX346264B_D0747.tif" />

1, ó2; and X is 3-azabicyclo [3.2.0] hept-3-¡lo, 2-azabicyclo [2.2.2] oct2-¡lo, 6-azaspiro [2.5] oct-6-yl, octahydro-2H -isoindol-2-yl, 3-azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindol-2-yl, or 1,4-dioxa8-azaspiro [4.5] dec-8-yl. In additional subgroups of compounds

D is

N

<img file="MX346264B_D0748.tif" />

Ί (^RM) independent g in which g is 0, 1, or 2; R_M is each fluoro, chloro, methyl, methoxy, trifluoromethyl, or

<img file="MX346264B_D0749.tif" />

trifluoromethoxy;

and it is as defined above. In additional compound subgroups D

<img file="MX346264B_D0750.tif" />

in which

R_M1 is each independently hydrogen, fluoro, chloro, or

<img file="MX346264B_D0751.tif" />

methyl and is as defined above (e.g. 3azabicyclo [3.2.0] hept-3-yl, octahydro-2H-isoindol-2-lo, 2azabicyclo [2.2.2] oct-2-yl,

6-azaspiro [2.5] oct-6-yl,

<img file="MX346264B_D0752.tif" />

249 azaspiro [5.5] undec-3-yl, 1,3-dihydro-2H-isoindole-2-ilo, T, 4-dioxa-8IMPI

KdklCANO INSTITUTE

FROM THE INDUSTRIAL FROMWAD azaspiro [4.5] dec-8-yl).

In other groups of compounds in accordance with the

Formula l_G and the above modalities and description of this

<img file="MX346264B_D0753.tif" />

a nitrogen-containing 4-8 membered monocyclic heterocycle (e.g. azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R_G2, in which R_G2 each occurrence is each independently halogen, -C (O) C-Cg alkyl, -Cí-Cg alkyl, -C ^ Cg halogenoalkyl, -O-C ^ Cg alkyl, or -O- Ο ^ Οβ haloalkyl; and Rm is each independently halogen, -Cj-Cg alkyl, -Ci-Cg halogenoalkyl, -O-Ct-C alkyl₆, or -O-halogenoalkyl of CpCg. In each group of compounds in accordance with the previous modalities

<img file="MX346264B_D0754.tif" />

is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R_G2, in which R_G2 each occurrence is each methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is each independently fluoro, chloro, or methyl. By

<img file="MX346264B_D0755.tif" />

250

<img file="MX346264B_D0756.tif" />

Rg2 is 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-1IMPI

INSTITUTO MEXICANO PE LA PROPERTY INDUSTRIAL example ¡lo, 2,6-dimethylpiperidin-1-yl, 4- (propan-2-yl) piperidin-1 -yl, 4-fluoropiperidin-1 -yl, 3,5-d¡met Lpiper¡n-1-yl, 4 (trifluoromethyl) piperid¡n-1-yl, 4-methylpiperidin-1-yl, 4-tertbutylpiperidin-1-yl, 2-oxopiperidin-1-yl, or 3, 3-dimethylazet¡d¡n-1-yl.

The present invention also features compounds of Formulas l_AND, If e &lt;g as described in the present application (including each embodiment described therein) and pharmaceutically acceptable salts thereof, in which:

R_and is selected independently each time it appears from -OR_s, -MR_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)SW₂R_s', -SO₂N (R_sR_s’),

-N (R_s)SW₂N (Rs'R_s"), -N (Rs) S (O) N (R_s'R_s”), -OS (O) -R_s, -BEAR)₂-R_s, -S (O)₂OR_s&gt; -S (O) OR_s, -OC (O) OR_S, -N (R_S) C (O) OR_S', -OC (O) N (R_sRs'), -N (Rs) S (O) -R_s', -S (O) N (R_sR_s'), -P (O) (OR_S)₂, = C (RsRs'), or -C (O) N (R_S) C (O) -R_S'; or C, -C alkyl₆ C alkenyl₂-C₆ or C alkynyl₂-C₆, each of which independently is optionally substituted each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, or cyano ; or carbocycle of C₃-C₁₂ or 3- to 12-membered heterocycle, each of which independently is optionally

<img file="MX346264B_D0757.tif" />

251

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY HBUSTR1AL substituted each time it appears with one or more substituents and selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, CyCe alkyl, alkenyl of C₂-C₆, C alkynyl₂-C₆, C halogenoalkyl_rC_6; C halogenoalkenyl₂-C₆, C halogenoalkynyl₂-C₆, -OR_s, -MR_s, -C (O) R_S, -C (O) OR_S, or -N (RsRs').

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 desirable due to one or more of the physical properties of the salt, such as increased pharmaceutical stability under certain conditions or desired solubility in water or oil. In some cases, a salt of the compound may be useful for the isolation or purification of the compound.

In cases where it is intended to administer a salt to a patient, the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, basic addition salts, and alkali metal salts.

Pharmaceutically acceptable acid addition salts can 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 acids. Examples of suitable organic acids include, but are not limited to, the classes of

<img file="MX346264B_D0758.tif" />

252 aliphatic, cycloaliphatic, aromatic, araliphatic organic acids,

IMPI

INSTITUTO MEXICANO Oí LA PROFIEDA ·! Mi »f h'TQlA * heterocyclyl, carboxylic, and sulfonic. Specific examples of appropriate organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, acid. anthranilic, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate benzenesulfonate, pantothenate toluenesulfonate, 2hydroxyethanesulfonate, sufanylate, cyclohexylaminosulfonate, alginic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorium, camphor sulfonate, cyclopentanepropionate, dodecyl sulfate, glucoheptane sulfate, 2-glyceryl sulfate, glucoheptane sulfate, 2-glyceryl sulfate, glucoheptane sulfate, glycerol palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Pharmaceutically acceptable basic addition salts include, but are not limited to, metal salts and organic salts. Non-limiting examples of suitable metal salts include alkali metal salts (group la), alkaline earth metal salts (group lia), and other pharmaceutically acceptable metal salts. Said salts can be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc. Non-limiting examples of appropriate organic salts can be made from tertiary amines and quaternary amine, such as

253

<img file="MX346264B_D0759.tif" />

tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine,

IMPI

INT1I1U ·· MORGAÑO

M INDUSTRIAL PROPERTY choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing groups can be quaternized 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, dibutyl, and diamyl sulfates), aralkyl halides (eg, benzyl and phenethyl bromides), and others.

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

The compounds or salts of the present invention can also be used in the form of prodrugs. Some prodrugs are aliphatic or aromatic esters derived from acid groups in the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups in the compounds of the invention. Hydroxyl group phosphate-type prodrugs are the preferred prodrugs.

The compounds of the invention can comprise asymmetrically substituted carbon atoms known as chiral centers. These compounds can exist, without limitation, as individual stereoisomers (eg, individual enantiomers or individual diastereomer), mixtures of stereoisomers

<img file="MX346264B_D0760.tif" />

254 (for example a mixture of enantiomers or diastereomers), or

IMPI

INSTITUTE M SX1CA NO

FROM! TO PROPERTY «mdustriai racemic mixtures. The compounds identified in the present application as individual stereoisomers are intended to describe compounds that are present in a form that is substantially free of other stereoisomers (eg, substantially free of other enantiomers or diastereomers). By the term "substantially free", it is meant that at least 80% of the compound in a composition is the described 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. In cases 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 that contain any stereoisomer of the chiral center.

The 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 chromatographic separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution.

IM-PI iwrnvrMexican m la monedad industrial

<img file="MX346264B_D0761.tif" />

255

Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantially optically pure materials and synthesis reactions that do not cause racemization or reversal of stereochemistry at chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthesis reaction can be prepared, for example, using chromatographic techniques as appreciated by those skilled in the art. Chromatographic resolution of the enantiomers can be achieved using chiral chromatography resins, many of which are commercially available. In a non-limiting example, the racemate is placed in solution and loaded onto the column containing a chiral stationary phase. The enantiomers can then be separated by HPLC.

Resolution of enantiomers can also be achieved by converting the enantiomers in a mixture into diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can be separated by column chromatography or crystallization / recrystallization. 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 are separated by chromatography, they can be

256

<img file="MX346264B_D0762.tif" />

regenerate individual enantiomers. Often the auxiliary

IMPI

OBLA COIN »INDUSTRIAL chiral 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 only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

Alternatively, the enantiomeric salts can be prepared in a mixture using any method known in the art, including treatment of the carboxylic acid with an appropriate optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / recrystallization of enantiomerically pure salts. Appropriate methods 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 cis (Z) and trans (E) isomers, and mixtures thereof, are intended to be encompassed within the scope of an indicated compound unless otherwise specified.

IMPI Mexican institute

D £ THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0763.tif" />

257 contrary. Furthermore, in cases where a compound exists in various tautomeric forms, a stated compound is not limited to any specific tautomer, but rather is intended to encompass all tautomeric forms.

Some compounds of the invention may exist in different stable conformational forms which are capable of separation. Torsional asymmetry due to restricted rotations around an asymmetric single bond, for example due to spherical hindrance or ring tension, can allow the separation of different conformers. The invention encompasses each conformational isomer of these compounds and mixtures thereof.

Some 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 described in general terms in the present application using standard nomenclature. For an indicated compound having asymmetric center (s), it is to be understood that all stereoisomers of the compound and mixtures thereof are encompassed by the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-trans isomers. In cases where an indicated compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms.

258

<img file="MX346264B_D0764.tif" />

Some compounds are described in the present application using

IMPI

MEXICAN INSTITUTE

Give the PROPERTY indi ist »i * i general formulas that include variables (for example, A, B, D, X,

Li, L₂, L_3i Y, Z, T, R_to or R_b,). Unless otherwise specified, each variable within that formula is defined independently of any other variable, and any variable that occurs more than once in a formula is defined independently each time it occurs. If the portions are described as independently selected from a group, each portion is selected independently of the other. Therefore, each serving may be identical to or different from the other serving or servings.

The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix C_x-C_Y,, in which "x" is the minimum number and "y" is the maximum number of carbon atoms in the portion. Thus, for example, "Cy-Cealkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Continuing the illustration, cycloalkyl of C₃-C₆means a saturated hydrocarbyl ring containing 3 to 6 ring carbon atoms. A prefix appended to a multi-component substituent only applies to the first component immediately preceding that prefix. To illustrate, the term carbocyclylalkyl contains two components: carbocyclyl and alkyl. Hence, for example, carbocycl¡l (C₃-C₆) -Ci-Ce alkyl refers to a carbocyclyl of C₃-C₆ attached to the parent molecular moiety through a C1-Cb259 alkyl group

<img file="MX346264B_D0765.tif" />

Unless otherwise specified, when a

IMPI

MEXICAN INSTITUTE

DE IA FROMHJAD INDUSTRIAL linker element links two other elements in a depicted chemical structure, the leftmost described component of the linker element is attached to the leftmost element in the depicted structure, and the rightmost described component of the linker element is attached to the element on the right in the depicted structure. To illustrate, if the chemical structure is -Ls-M-Ls'- and M is -N (R_B) S (O) -, then the chemical structure is -L_s-N (R_b)SUN_s'-.

If a linker element in a depicted structure is a link, then the element to the left of the linker element is directly linked to the element to the right of the linker element by a covalent bond. For example, if a chemical structure is represented as -L_s-ML_s'- and M is selected as the bond, then the chemical structure will be -L_s-L_s'-. If two or more adjacent linker elements in a depicted structure are links, then the element to the left relative to these linker elements is directly linked to the element to the right relative to these linker elements by a covalent bond. For example, if a chemical structure is represented as -L_s-M-Ls'-M'-L_s-, and M and L_s'are selected as bonds, then the chemical structure will be -L_s-M'-L_s-. Similarly, if a chemical structure is represented as -L_s-ML_s'-M'Ls-, and M, Ls' and M' are bonds, so the chemical structure will be -Ls-Ls-.

260 IMPI ^

INSTTTÜT · MWICANO r?

OF THE FORMAD Ota nwrmu

When a chemical formula is used to describe a radical, the hyphen (s) indicate the portion of the radical that has the free valence (s).

If a radical is described as optionally substituted, the radical may be substituted or unsubstituted. If a portion is described as optionally substituted with up to a particular number of non-hydrogen-type radicals, said portion may be unsubstituted, or substituted with up to said particular number of non-hydrogen-type radicals or up to the maximum number of substitutable positions in the portion, whichever is less. Thus, for example, if a portion 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 only with up to as many non-hydrogen radicals as substitutable positions. have the heterocycle. To illustrate, tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen radical. To continue the illustration, if an amino nitrogen is described as optionally substituted with up to two non-hydrogen type radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen type radicals, while a secondary amino nitrogen it will be optionally substituted with up to only one non-hydrogen radical.

261

<img file="MX346264B_D0766.tif" />

In cases where a portion is substituted with oxo or

IMPI

INSTITUTO MEMCANO DE LA MIOHEDAD industeial thioxo, this means that the portion contains a carbon atom covalently bonded to at least two hydrogens (for example,

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 double bonds. Each carbon-carbon double bond can have cis or trans geometry within the alkenyl moiety, relative to the groups substituted on the carbons of the double bond. 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 can be straight 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, t-butyl, pentyl, iso-amyl, and hexyl.

The term "alkylene" indicates a divalent saturated hydrocarbyl chain which can be straight or branched. Representative examples of alkylene include, but are not limited to, -CH₂-,

IMPI ^ ίΝτπηπν Mexican

OF THE rtOREDAD ixaotiw

-CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and -CH₂CH (CH₃) CH₂-.

The term "alkynyl" means a straight or branched hydrocarbyl chain containing one or more 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 can be linear or branched and which has at least one carbon-carbon triple bond. Representative alkynylene groups include, by way of example, -C = C-, -CsC-CH₂-, -C = C-CH₂-CH₂-, -CH₂-C ^ C-CH₂-, -Csc-CH (CH₃) - and -CH₂-ChC-CH (CH₂CH₃)-.

The term "carbocycle or carbocyclic or carbocyclyl" refers to a saturated (eg cycloalkyl), partially saturated (eg cycloalkenyl or cycloalkynyl), or fully unsaturated (eg aryl) ring system containing zero heteroatomic ring atoms. Ring atoms or ring members are the atoms joined together to form the ring or rings. A carbocyclyl can be, without limitation, a single ring, two fused rings, or bridged or spiro structured rings. A substituted carbocyclyl can have any cis or trans geometry. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl indanyl, 1,2,3,4 ™ IMPI ^ ιντπτΟτ · Mexican

H THE PMHEBAD

INDUSTRIAL tetrahydronaphthyl, indenyl, isoindenyl, decalinyl, and norpinanyl. A carbocycle group can be attached to the parent molecular moiety through any substitutable carbon ring atom. In cases where a carbocycle group is a divalent moiety that bonds two other elements in a depicted chemical structure (such as A in Formula I), the carbocycle group can be attached to the other two elements through any two atoms of ring substitute them. Likewise, in cases where a carbocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I), the carbocycle group can be attached to the other three elements through of any three substitutable ring atoms, respectively.

The term "carbocyclylalkyl" refers to a carbocyclyl group attached to the parent molecular moiety through an alkylene group. For example, carbocycl¡l (C3-C₆) -alkyl of Ο, -Οκ refers to a carbocyclyl group of C₃-C₆ attached to the parent molecular moiety through an alkylene of Ο₄-Ο₆.

The term "cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclyl moiety having zero heteroatomic ring members. 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 heteroatomic ring members. The

IMPI

UVSTTTVTO MEXICAN

ΚΜΗΙβηίΒΑΖ »

<img file="MX346264B_D0767.tif" />

264 Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, decalinyl, and norpinanyl.

The prefix halogen indicates that the substituent to which the prefix is ​​attached is substituted with one or more independently selected halogen radicals. For example, Ci-C haloalkyl₆ means an alkyl substituent of 0_Γ0₆in which one or more hydrogen atoms are replaced with independently selected halogen radicals. Non-limiting examples of geno!-De haloalkyl₆ They include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted with more than one halogen radical, said halogen radicals may be identical or different (unless otherwise indicated).

The term "heterocycle or heterocycle or heterocyclyl" refers to a saturated (eg, heterocycloalkyl), partially unsaturated (eg, heterocycloalkenyl or heterocycloalkynyl), or fully unsaturated (eg, heteroaryl) ring system in which at least one of the ring atoms is a hetero atom (i.e. nitrogen, oxygen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocycle can be, without limitation, a single ring, two fused rings, or structured rings

<img file="MX346264B_D0768.tif" />

265 IMPI

Μππυιο Mkican

MUFMHEDAD

IMWSTIUAL in bridge or spiro. A heterocycle group can be attached to the parent molecular moiety via any substitutable carbon or nitrogen atom or atoms. In cases where a heterocycle group is a divalent moiety that links two other elements in a depicted chemical structure (such as A in Formula I), the heterocycle group may be attached to the other two elements through any two atoms of replaceable ring. Likewise, in cases 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 other three elements through any three substitutable ring atoms, respectively.

A heterocyclyl can be, without limitation, a monocycle containing a single ring. Non-limiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolylthiolyl, tetrazolothiolyl, oxathiazolyl thiolyl, tetrazolothiolyl, oxathiolithiolyl, , thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as azoxynyl), 1,2,5-oxadiazolyl (also known as furazanyl), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4 oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4-dioxazolyl),

266

<img file="MX346264B_D0769.tif" />

oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl),

IMPI

WSTrtVI · MEXICAN

OF U INDUSTRIAL AGE dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as 1,2-diazinyl), pyrimidynyl (also known as 1,3-diazinyl), and pyrazinyl (also known as 1,4-diazinyl) ), piperazinyl, triazinyl (including striazinyl (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, 1,3,2oxazinyl, 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 1,4,2oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl, and diazepinyl.

A heterocyclyl can also be, without limitation, a bicyclo containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl , thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido¡ [3,2-b] -pyridinyl, pyrido¡ [3,2-b] -pyridinyl, pyrido¡ [3,2-b] -pyridinyl, dnlo, and pyrido [4,3-b] pyridinyl), pyridopyrimidine, and pteridinyl. Other non-limiting examples of fused ring heterocycles include benzofused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as pseudoindolyl), isoindazolyl (also known

- IMPI ^ iNsrrruTBMBucANo

OF THE PROPERTY

INDUSTRIAL such as benzpyrazolyl or indazolyl), benzazinyl (including quinolinyl (also known as 1-benzazinyl) and isoquinolinyl (also known as 2-benzazinyl)), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cynolinyl (also known as 1,2- benzodiazinyl) and 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 benzothiophenyl, thionaphthenyl, and benzothiofuranyl), isenobenothionezothienyl (also known as isbenzothiofuranyl), isenobenothionyl istenobenothionyl (also known as isenobenothionezine) ), benzothiazolyl, 4,5,6,7tetrahydrobenzo [d] thiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl), and tetrahydroisoquinolinyl.

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

A heterocyclyl can comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom or atoms are oxidized to SO or SO₂. The heteroatom (s)

263 IMPI ^

Mexican INSTITUTE

OF THE PROPERTY

INDUSTRIAL * Nitrogen * in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to the N-oxide.

Furthermore, the nitrogen heteroatom (s) may or may not be N-protected.

in a chemical formula it refers to a single or double bond.

The term "pharmaceutically acceptable" is used as an adjective to mean that the modified noun is appropriate for use as a pharmaceutical product or as part of a pharmaceutical product.

The term "therapeutically effective amount" refers to the total amount of each active substance that is sufficient to show significant benefit to the patient, for example a reduction in viral load.

The term prodrug refers to derivatives of the compounds of the invention which have groups susceptible to chemical or metabolic cleavage and are converted, by solvolysis or under physiological conditions, into the compounds of the invention which are pharmaceutically active in vivo. A prodrug of a compound can be formed in a conventional manner by reacting a functional group of the 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). The ™ IMPI ^

MEXICAN INSTITUTE

OF THE RR «F1EDAD Ce« ^ 3

INDUSTRIAL prodrugs include acid derivatives well known to those practicing the art, such as, for example, esters prepared by reacting the parent acidic compound with an appropriate alcohol, or amides that are prepared by reacting the parent acidic compound with an appropriate 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, either organic or inorganic. This physical association often includes hydrogen bonding. In some cases, the solvate is capable of isolation, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. Solvate encompasses both solution phase solvates and isolatable solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, and methanolates.

The term "N-protecting or N-protected group" refers to those groups that can protect an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3^to ed., John Wiley &amp; Sons, NY (1999). Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2

270 IMPI

INJTlTUT · MEXICAN ·

Say THE PROPERTY Cm&gt; 3K

INDUSTRIAL - X chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, onitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or ptoluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S (O) -) or t-butylsulfinyl (t-Bu-S (O) -); Carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, pbromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4,5-methoxy-benzyloxycarbonyl, 4,5-methoxy-benzyloxycarbonyl, 4,5-methoxybonyloxycarbonyl, 4,5-methoxybonyloxycarbonyl, 4, 5-methoxy-benzyloxycarbonyl dimethoxybenzyloxycarbon,

3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenyloxycarbonyl) -1-methylethoxycarbonyl, d¡methyl I-3,5-d¡methoxy benzyloxycarbonyl, benzhydryloxycarbonyl, tbutyloxycarbonyl, di- isopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, alkyl groups such as benzyl, pmethoxybenzyl, triphen i I methyl, or benzyloxymethyl; p-methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

The abbreviations that have been used in

IMPI βΤΠυΐφΜΙΧΚΛΝ ·

M THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0770.tif" />

271 descriptions of Reaction Schemes, Intermediaries and

Examples that follow are: Ac for acetyl; APCI for chemical ionization at atmospheric pressure; ac or ac. for aqueous; atm for atmosphere; Boc for t-butoxycarbonyl; Bu for butyl; t-Bu or tert-butyl for tertiary butyl; Cbz for benzyloxycarbonyl; dba for dibenzylideneacetone; DCI for chemical ionization by desorption; DDQ for 2,3-dichloro-5,6-dicyan-p-benzoquinone; DEPBT for 3 (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one; DIBAL for di-isobutylaluminum hydride; DMA for Ν, Ν-dimethylacetamide; DME for 1,2-dimethoxyethane; DMF for Ν, Ν-dimethylformamide; DMSO for dimethyl sulfoxide; DMPLI for 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone; dppf for 1,1'-bis (diphenyl phosphino) ferrocene; EDO, EDAC or

EDCI for N-IS-dimethylaminopropylj-N'-ethylcarbodiimide hydrochloride; ee for enantiomeric excess; ELSD for evaporative light scattering detector; ESI for electrospray ionization; Et for ethyl; Et₃N for triethylamine; EtOAc for ethyl acetate; EtOH for ethanol; Et₂Or for diethyl ether; eq or equiv for equivalents; Fmoc for 9-fluorenylmethoxycarbonyl; HATU for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; HOBt for 1-hydroxybenzotriazole; HPLC for high performance liquid chromatography; HOBt for 1-hydroxybenzotriazole; LCMS for liquid chromatography / mass spectrometry; mCPBA for m-chloroperoxybenzoic acid; Me for methyl; MeOH for methanol; OAc for acetate; Ms for methanesulfonyl; OTF for triflate or trifluoromethanesulfonate; PDC for dichromate

272

IMPI

INSTITUTO MEXICA NO DE LA PROPERTY INDUSTRIAL pyridinium; i-Pr for isopropyl; Ph for phenyl; PPh3 for triphenylphosphine; Kg / cm² o Kg / cm² man. for kilogram per square centimeter or kilogram per square manometric centimeter; PTFE for polytetrafluoroethylene; PXPd for [(t-Bu)₂PCI] 2PdCI₂, PyBOP for (benzotriazol-1-yloxy) tripyrrrolidinophosphonic hexafluorophosphate; SEM for 2- (trimethylsilyl) ethoxymethyl; T3P for propane phosphonic acid anhydride; Tf for trifluorosulfonyl; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TLC for thin layer chromatography; Troc for 2,2,2-trichloroethoxycarbonyl; v / v for volume / volume; % w for percent by weight; w / v for weight / volume; w / w for weight / weight; XantFos for 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene;

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 Reaction Scheme I starting from compounds of Formula II (eg, n = 0 to 8), of Formula V (X₄ can be, for example, O or NR_TO, in which R_TO is as previously described in the present application and is preferably H or R_AND as defined above such as Ci-C alkyl₆, 3- to 12-membered carbocycle or heterocycle, -C (O) R_S, -C (O) OR_S, -C (O) N (R_SR_S'), -SO₂N (R_sRs'), -S (O)₂OR_s, -S (O) OR_s, -S (O) N (R_sR_s'), or an appropriate protecting group such as Boc or Fmoc), or of Formula VIII (E may be, for example, 3- to 7-membered carbocycle or heterocycle and is optionally substituted with one or more R_TO), in which A, B, D, Y, Z and R_TO they are as described above.

273 IMPI ^

MEXICAN INSTITUTE

I heard THE FROMEDAD &lt;

INDUSTRIAL

The 1,4-diketones II, V, and VIII can be reduced to 1,4-diols using the methods described below, and the resulting enantiomerically enriched, or meso, racemic 1,4-diols can be converted to the dimesylates III, VI, or IX, or alternatively in the ditriflates, ditosylates, or dihalides by the methods described below. Dimesylates III, VI, and IX, ditriflates, ditosylates, or dihalides can be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline , 4-chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines, or allylamine, under the conditions described below to obtain the compounds of the invention. Ly and L₂ they can be readily introduced into Formulas II, V and VIII, as appreciated by those skilled in the art in light of the present invention. Similarly, you can use DL₃-NH₂instead of D-NH₂, as appreciated by those skilled in the art.

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vn

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IMPI

INSTITUTE ΜβΚΛ! »Ο

DS LA MOHEDA »

INDUSTRIAL

274

<img file="MX346264B_D0773.tif" />

REACTION SCHEME I

As another non-limiting example, the compounds of the present invention can be prepared starting from the compounds of Formula II and Formula III as shown in Reaction Scheme II. 1,4-diketones such as Formula IV can be prepared using known methods (see Nevar, et al., Synthesis: 1259-1262 (2000), such as the reaction of abromoketones such as Formula II with methyl ketones such as Formula III in the presence of an appropriate Lewis acid such as ZnCl₂ or Ti (OiPr)₄. For example the 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 about room temperature can provide the IV diketones. 1,4-diketones IV can be reduced to 1,4-diols such as V by the action of NaBH₄, LiAIH₄, or DIBAL. Alternatively, enantioselective reduction of 1,4-diketones such as Formula IV can be achieved by analogy with reported methods (see Chong, et al., Tetrahedron: Asymmetry 6: 409-418 (1995), Li, et al., Tetrahedron

275

<img file="MX346264B_D0774.tif" />

63: 8046-8053 (2007), Aldous, et al., Tetra h ^ rirnn- Asvmmetrv

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRY CURRENCYf

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 an appropriate ruthenium (II) catalyst, such as [RuCl2 {(R) -BINAP} {(R, R) -DPEN}] (BINAP = 2,2'-bis (d¡ aryphosphine) -1, Γbinaphthyl; DPEN = 1,2-diphenylethylenediamine). IV diketones (1 equivalent) can be reduced with NaBH₄ (3 equivalents) in solvents such as tetrahydrofuran with heating to about 50 ° C. Diketones IV (1 equivalent) can be enantioselectively reduced after addition to a mixture made from Ν, Ν-diethylaniline-borane (approximately 2 equivalents), trimethyl borate (approximately 0.2 equivalents) and either (S) α, α-diphenyl 2-p¡rΓOl¡din-methanol or (R) a, a-diphenyl-2-pyrrolidine-methanol (approximately 0.17 equivalents) in a solvent such as THF at temperatures ranging from about 10 ° C to about 30 ° C (Synthesis 2507-2510 (2003)). The resulting enantiomerically enriched, racemic, 1,4-diols or meso V can be reacted with methanesulfonyl chloride or methanesulfonic anhydride to provide the dimesylate of Formula VI. For example, diols V (1 equivalent) can be reacted with methanesulfonic anhydride (approximately 2.5 equivalents) in the presence of such a base

<img file="MX346264B_D0775.tif" />

²⁷⁶ IMPI

MEXICAN INSTITUTE

DIlAPKOmOA · induxtrA as di-isopropylethylamine (about 4 equivalents) in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran at temperatures starting from about -15 ° C to -25 ° C and increasing to about room temperature. Alternatively, Formula V can be converted to a ditriflate or ditosylate through the action of ptolenesulfonyl chloride or triflic anhydride, or even a dihalogenide such as a dibromide or dichloride through the action of PPh.₃ in the presence of CCI₄ or CBr₄, or through the action of SOCI₂, POCI₃, or PBr₃. The dimesylate, ditriflate, ditosylate, or dihalogenide can be reacted with an amine, such as 4-fluoroaniline (as shown for illustration in Reaction Scheme II), with or without a cosolvent such as DMF at room temperature up to 100 ° C, to produce pyrrolidines such as Formula VII. Dimesylate VI (1 equivalent) (or alternatively ditriflate, ditosylate, or dihalogenide) can be reacted with between 1 to 20 equivalents of a D-NH amine₂, such as, for example, an aniline substituted 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 produce pyrrolidines such as Formula VII. In cases where fewer D-NH amine equivalents are used₂ (ie, 1-2 equivalents), a base such as diisopropylethylamine can be added to promote the reaction. In some cases, the amine may be used in large excess (i.e., as a solvent for

277

<img file="MX346264B_D0776.tif" />

IMPI

MEXICAN INSTITUTE

OBLA COIN · iNDumui reaction). For example, the reaction of a dimesi + a + e - ^ - with excess aniline (approximately 6.5 equivalents) can be effected by heating at 65 ° C in 2-methyltetrahydrofuran until the reaction is complete. Numerous substituted anilines can be reacted with the dimesylate of Formula VI, including but not limited to, 3-fluoro-4- (piperidin-1-yl) aniline, 3,5-difluoro-4 (piperidin-1- ¡L) aniline, 3,5-difluoro-4- (4-phenylp¡perid¡n-1-yl) aniline, 3d¡fluoro-4- (4-phen¡lp¡per¡d ¡N-1-yl) an¡l¡na, 4- (4-phenylpiper¡din-1-yl) aniline, 4-cyclopropylene line, 4-cyclopropyl-2-fluoroaniline, 4-cyclopropyl-3 , 5-difluoroaniline, 4-cyclohexyl-3-fluoroaniline, biphenyl-4-amine, 4- (pyridin2-¡l) aniline, 3,5-dichloro-4- (piper¡d¡n-1-yl) aniline, 4- (4,4-dimethylpiperidin-1-yl) -3,5-difluoroaniline, 4- (4,4-fluoropiperidin- 1-yl) 3,5-difluoroaniline, 3-methyl 4- (p¡per¡d¡n-1 -yl) aniline, 2,5-difluoro-4 (piperidin-1-yl) aniline, 4 - (3,5-Dimethylpiperidin-1 -yl) -3,5-difluoroanilin, 4- (2,6-dimethylpiperidin-1-¡l) -3,5-d¡fluoroan¡ line, 2,3,5-trifluoro-4 (piperidin-1-yl) an ylin, 3,5-difluoro-4- (4-isopropylpiperidin-1-yl) aniline, 3,5-difluoro-4- (4-methylpiperidin-1-yl) aniHna, 3,5-Difluoro-4- (4 (trifluoromethyl) p¡per¡d¡n-1-¡l) aniline, 4- (4-tert-butylpiperidin-1-i 1) -3,5-difluoroaniline, 3 , 5-Difluoro-4- (6-azaspiro [2.5] octan-6-yl) aniline, 4- (2azabicyclo [2.2.2] octan-2-yl) -3,5-difluoroaniline, 4- (3,3 -dimethylazetidin1-yl) -3,5-difluoroaniline, 4-tert-butylaniline, 4-ethoxyaniline, 4-phenoxyaniline, 1 - (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) an yline, 4- (oxazol-2-yl) aniline, 4- (2-fluoropyridin-4

278 IMPI Mexican institute

OF HYOHEDAD

INDUSTRY!

yl) a ni line, 3,4-difluoroaniline, 4-chloro-3-fluoroaniline, 3-fluoro-4 (methylsulfonyl) aniline, 4- (3-azabicyclo [3.2.0] heptan-3-yl ) -3,5-difluoroaniline, 4 - ((3-ethyloxetan-3-¡l) methoxy) aniline, 4-cyclopropyl-3,5-difluoroaniline, 4- (1,3-dioxan-5-yloxy) aniline, 3, 5-Difluoro-4 (octahydro¡soindole-2-¡l) aniline, 4 - ((1,3-dioxolan-4-¡I) methoxy) aniline, 4 ((S-ethyloxetan-S-iOmethoxO-SS -difluoroaniline, 4 (pentafluorosulfanyl) aniline, N1-tert-butyl-2-fluorobenzene-1,4-diamine, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines, allylamine, or anilines that are listed in or that can be made using General Procedures 1, 1.1, or 1.2. The dinitro of Formula VII can be reduced to the diamine of the

Formula VIII using Fe in the presence of NH₄CI, HCI, 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 B¡CI₃, SbCI₃, N¡CI₂, Cu₂CI₂, or CoCI₂) in a solvent such as ethanol or THF. For example compounds Vil (1 equivalent) can be reduced to VIII by reaction with iron powder (approximately 6 equivalents) and ammonium chloride in a 1: 1 mixture of THF and ethanol with heating to approximately 60-80 ° C. Alternatively, Formula VII can be reduced to the product of Formula VIII by hydrogenation in the presence of an appropriate catalyst, such as a palladium or platinum or nickel-Raney catalyst. For example the reduction of Vil to VIII can be carried out by exposure to 2.11 kg / cm² hydrogen gas gauges in the presence of nickel-

<img file="MX346264B_D0777.tif" />

279

Raney Grace 2800 in a solvent such as tetrahydrofuran with

IMPI

INSTITUTO M BUCAHO

OF THE INDUSTRIAL NEED agitation. The diamine of Formula VIII can be reacted with an appropriately protected proline acid (Boc shown, although Cbz, Troc, or Fmoc can be substituted) in the presence of a reagent for peptide coupling, 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 N-methylmorpholine, Hunig's base, pyridine, 2, 6-lutidine, or triethylamine, to produce Formula IX. For example, the reaction of VIII (1 equivalent) with 1- (tertbutoxycarbonyl) pyrrolidine-2-carboxylic acid (2.5 equivalents) and HATU (2.5 equivalents) in the presence of di-isopropylethylamine (3 equivalents) in DMSO at about room temperature can provide the product IX. Removal of Boc protecting groups to produce X can be accomplished by treatment with an acid, such as TFA, HCI, or formic acid. For example, the reaction of IX (1 equivalent) with TFA: CH₂CI₂ (1: 1) at room temperature can provide compounds X. Compounds XI can be prepared by coupling 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- (methoxycarbonylamine) -3 acid, 3-d¡metalbutanoic_&gt; 2-cyclohexyl-2 (methoxycarbonylamine) acetic acid, 2- (methoxycarbonylamino) -2IMPI ιήπιυιυ mmican acid

Dt THE PROPERTY

INDUSTRIAL

<img file="MX346264B_D0778.tif" />

280 (tetrahydro-2H-pyran-4-yl) acetic acid, or the acids listed under

General Procedure 19. Alternatively, diamine VIII can be reacted directly with an appropriately N-substituted proline in the presence of a reagent for peptide coupling 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-type base such as N-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to directly produce compounds XI. For example, VIII (1 equivalent) can be reacted directly with 1- (2- (methoxycarbonylamine) -3-methylbutanoyl) pyrrolidin-2-carboxylic acid (approximately 2 equivalents) and T3P (approximately 2.8 equivalents) in presence of di-isopropylethylamine (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 above sequence illustrates the synthesis of particular compounds of the invention XI having a substituted proline group at Y and Z (i.e., R₂ and Rs taken together with the atoms to which they are attached, and R₉ and R₁₂ taken together with the atoms to which they are attached, they each form a 5-membered heterocycle). It is understood that analogous synthetic procedures can be used to make the compounds of the invention in which Y, Z, R₂, R₅, R₉, and R₁₂ they are different from those shown and described in Reaction Scheme II.

281

<img file="MX346264B_D0779.tif" />

IMPI

IMTl UI I · M * 1CANO

DE LA nonEDA * industrial

F

<img file="MX346264B_D0780.tif" />

in each Formula within Reaction Scheme II can be replaced with

<img file="MX346264B_D0781.tif" />

in which D is defined above, and said compounds can be easily prepared according to the procedure described in Reaction Scheme II (including making compound XI directly from compound

VIII). Similarly, compounds of Formula XII can be prepared from compounds of Formula X or directly from compounds of Formula VIII.

<img file="MX346264B_D0782.tif" />

<img file="MX346264B_D0783.tif" />

282

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX346264B_D0784.tif" />

<img file="MX346264B_D0785.tif" />

xn

REACTION SCHEME II

Even 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 Reaction Scheme III, in which A, B, D, Y, and Z are as described above, using conditions similar to those described above for the preparation of IV in Reaction Scheme II. Similarly, the resulting 1,4-diketone IV can be reduced to 1,4-diols V using the

283

<img file="MX346264B_D0786.tif" />

Methods described above for Reaction Fsnuema II.

The resulting enantiomerically enriched, or meso, racemic 1,4-diols V can be converted to dimesylate VI or alternatively to a ditriflate, ditosylate, or dihalogenide by the methods described above. Dimesylate VI, ditriflate, ditosylate, or dihalogenide can be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines, or allylamine, under the conditions described above to produce the compounds of the invention. Alternatively, compounds such as VIII, in which R is a group such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, can be treated with reagents useful for removal of the R group (rhodium catalyst such as Rh ( Rh₃P)₃CI for R = allyl, treatment with an acid such as TFA or HCI 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 can be reacted with an aryl halide or triflate such as X (iodide shown for example) using the Buchwald-Hartwig 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 XantFos) and a base (such as sodium bis (trimethylsilyl) amide, potassium tert-butoxide, or K₃PO₄) to produce the compounds of the present

284 IMPI ^

WSTfTVT · MUtICAN t »eVINDUSTRIAL coin X ™ invention. Alternatively, the compounds of the present invention can be obtained by reacting 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 reductive amination can be effected through the use of hydrogenation in the presence of an appropriate catalyst, such as a palladium or platinum or Raney nickel catalyst. 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 produce the compounds of the present invention.

<img file="MX346264B_D0787.tif" />

π m

<img file="MX346264B_D0788.tif" />

<img file="MX346264B_D0789.tif" />

<img file="MX346264B_D0790.tif" />

<img file="MX346264B_D0791.tif" />

285

IMPI

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY

<img file="MX346264B_D0792.tif" />

<img file="MX346264B_D0793.tif" />

IX

YH A l H í B} - Z

...... \ _ f κ

<img file="MX346264B_D0794.tif" />

VHI

R = allyl or substituted benzyl

REACTION SCHEME III

As a further non-limiting example, Compounds of XIII can be prepared starting from compounds of Formula II and Formula III as shown in Reaction Scheme IV, in which X₅ in Formula II and Formula III it represents a halogen (eg, Cl, Br, or F) or a nitro group. Additionally, each phenyl ring can be substituted with X₁₃, in which X₁₃ is X₅, H, alkyl, haloalkyl, alkoxy, or haloalkoxy. 1,4-diketones such as IV can be prepared using known methods described above for the preparation of IV for Reaction Scheme II. 1,4-Dketones IV can be reduced to 1,4-diols such as V by the action of NaBH₄, L¡AIH₄, or DIBAL. By way of

286

IMPI

INSTITUTO MEXICANO DE LA FKOREDAD INBUSTIUAl alternative, enantioselective reduction of 1,4-diketone such as IV can be achieved by the methods described above for the preparation of V in Reaction Scheme II. As described for Intermediate 20D, chiral reduction can proceed with lower stereoselectivity with an X substituent₁₃ additional on the phenyl ring. The resulting enantiomerically enriched, or meso, racemic 1,4-diols V can be reacted with methanesulfonyl chloride or methanesulfonic anhydride to provide the dimesylate VI. Alternatively V can be converted to a ditriflate or ditosylate by the methods described above for Reaction Scheme II. The dimesylate, ditriflate, ditosylate, or dihalogenide can be reacted, analogously to Reaction Scheme II, with a D-NH amine₂ including but not limited to those amines described or mentioned in Reaction Scheme II to produce Vil. When X₅ in Formula VII is nitro, nitro groups can be reduced to the tetraamine product IX using Fe in the presence of NH₄CI, HCI, 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 B¡CI₃, SbCI₃, NiCI₂, Cu₂CI₂, or CoCI₂) in a solvent such as ethanol or THF. Alternatively, Vil (X₅ = nitro) can be reduced to product IX by hydrogenation in the presence of an appropriate catalyst, such as a palladium or platinum or Raney nickel catalyst. Alternatively, compounds Vil in which X₅ = halogen can be reacted with ammonia (R = H) or a

<img file="MX346264B_D0795.tif" />

IMPI

INSTIIUI * MEXICAN

OF THE INDUSTRIAL AGE

287 amine bearing an appropriate protecting group (R = such as 4-methoxybenzyl or 2,4-dimethoxybenzyl substituted benzyl • - · '. or R = allyl). The resulting VIII products can be treated with a reagent useful for removal of the protecting group R (rhodium catalyst such as Rh (Ph₃P)₃CI for R = allyl, treatment with an acid such as TFA or HCI for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to produce product IX. Formula IX can be reacted with an appropriately protected proline acid (Boc shown, although Cbz, Troc, or Fmoc can be substituted) in the presence of a reagent for peptide coupling, 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-type base, such as N-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to produce X as a mixture of the amide products. Although Formula X shows that the reaction takes place in an NH group₂specific, the reaction can take place in any of the NH₂. Conversion to the benzimidazole compound XI can be achieved by heating X in acetic acid (50-100 ° C). Alternatively, XI can be prepared by reacting 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 Boc protecting groups from XI (achieved by treatment with an acid, such as TFA, HCI, or formic acid ), the compounds of the present invention can be

IMPI

IN JI11U Γ * MEXICAN

288 prepare by coupling the resulting diamine XII with an acid of choice using the peptide coupling reagents and standard conditions described above for Scheme of F

Reaction II to produce XIII. in each Formula within the

Reaction Scheme IV can be replaced with in which

D was defined above, and such compounds can be easily prepared according to the procedure described in Reaction Scheme IV. Compounds of Formula XIV can be prepared in a similar manner from compounds of Formula XII. When subjected to the synthetic procedures in Reaction Scheme IV, enantiomerically enriched diols V can produce mixtures containing varying amounts of cis and trans stereoisomeric pyrrolidines Vil. Stereoisomeric pyrrolidines can be separated according to standard chromatographic techniques. Alternatively, such separations can be carried out at a later stage in the synthesis process including the steps of the

Reaction Schemes XIII and XIV, or after the final step.

<img file="MX346264B_D0796.tif" />

REACTION SCHEME IV

<img file="MX346264B_D0797.tif" />

IMPI βρτπντο m * cano

Death

INDUSTRIAL

290

Alternatively IX in Reaction Scheme IV can be prepared from a compound of Formula II as shown in Reaction Scheme V. Compound VIII of Reaction Scheme II can be treated with an acylating agent such as acetyl chloride or acetic anhydride to produce compound II (Reaction Scheme V). Nitration of compound II to provide III can be achieved 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 NO.₂BF₄. Removal of the acetamide protecting group can be accomplished by treatment with Boc anhydride in the presence of DMAP to produce IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or LiOH) to remove the acetyl group and a strong acid. such as TFA or HCI to remove the Boc protecting group to provide V. Nitro groups in V can be reduced to amino groups using the methods described above for F

Reaction Scheme IV to provide IX. in each Formula within Reaction Scheme V can be replaced with

<img file="MX346264B_D0798.tif" />

in which D is defined above, and said compounds can be easily prepared according to the procedure described in Reaction Scheme V.

<img file="MX346264B_D0799.tif" />

IMPI

MUUCAN INSTITUTE OF FAOFIEDAI? IMCRFSTWIAl

<img file="MX346264B_D0800.tif" />

TQ

AcHN ^ · '· ?. I r ^ X ^ NHAc

VN_v J, U

OR₂N '___f NO, m

F

<img file="MX346264B_D0801.tif" />

Boc. Λ zAcN-, a 'uo #

<img file="MX346264B_D0802.tif" />

IX in Reaction Scheme IV

REACTION SCHEME V

Even as another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II as shown in Reaction Scheme VI, in which A, B, D, Y, and Z are as described. previously. A 1,4-diketone compound of the Formula II (prepared as described in Reaction Scheme III) can be reacted with an amine, including but not limited to

292

<img file="MX346264B_D0803.tif" />

a, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3IMPI

INJTHUrt »ΜβΤΆΝΟ

MU ^ ROniDAD wousnuAi fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkylamines, cycloalkylamines, substituted benzylamines, or allylamine, under acid-catalyzed conditions, such as acetic acid, TFA, formic acid, or HCI, to produce the compounds of the invention.

<img file="MX346264B_D0804.tif" />

<img file="MX346264B_D0805.tif" />

B, i — z

REACTION 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 Reaction Scheme VII. A compound of Formula II, in which R_x is a halogen, such as bromine, chlorine, or iodine, or a triflate or nonaphlate can be converted to a boronic acid or ester such as Formula III, using chemistry analogous to that of Reaction Scheme II to prepare Vil (in Reaction Scheme II); for example, starting with 1- (4-bromophenyl) ethanone and 2-bromo-1- (4-bromophenyl) ethanone. A compound of Formula II, in which R_x is a halogen, such as bromine, chlorine, or iodine, or a triflate or nonaphlate can be converted to a boronic acid or ester such as Formula III, (for example, a cyclic pinacholate ester) in which R is hydrogen, methyl, ethyl, or a cyclic pinacholate ester. For example a

293 compound of Formula II can be transformed into a compound of

<img file="MX346264B_D0806.tif" />

III by treatment with pinachol-borane in the presence of a catalyst such as, for example, tris (dibenzylideneacetone) palladium (0), and a ligand such as, for example, tri-t-butylphosphine, in solvents such as, for example example, tetrahydrofuran, dioxane, or toluene at temperatures ranging from room temperature to about 130 ° C. Alternatively, compound II can be reacted with bis (pinacholate) diboro in the presence of a catalyst such as, for example, Combifos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA), dichloro adduct [1,1 ' bis (diphenylphosphino) ferrocene] palladium (ll) -dichloromethane, or palladium acetate in the presence of a ligand such as, for example, 2-dicyclohexyphosphine-2^,, 4 ', 6'-tri-isopropylbiphenyl (XFos), and a base such as, for example, potassium acetate in solvents such as, for example, toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide at temperatures from about 60 to about 130 ° C to produce compound III. Alternatively, a compound of Formula II can be reacted with an organolithium reagent, such as n-BuLi, sec-BuLi, or t-BuLi, followed by reaction with trimethyl borate or triethyl borate, to produce a compound of Formula III.

A compound of Formula III in Reaction Scheme VII can be coupled with a compound of Formula IV, in which R_AND is a halogen, such as bromine, chlorine or iodine, under Suzuki reaction conditions to provide a compound of the ²⁹⁴ IMPI ^

INSTITUI MBBOUEO

OF THE PROPERTY

INDUSTRIAL

Formula V. Such conditions include, for example, the use of a palladium catalyst such as, for example, tris (d¡benzylidineacetone) palladium (0), palladium acetate, bis (triphenylphosphine) palladium (II) chloride, tetrakis (triphenylphosphine) palladium, or dichloro [1, r-bis (diphenylphosphine) ferrocene] palladium (ll) -dichloromethane adduct; a base such as, for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate, 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 Boc protecting groups from V can be accomplished by treatment with an acid, such as TFA, HCI, or formic acid. Some compounds of the present invention such as VI can be prepared by coupling the resulting amino compounds with an acid of choice using standard peptide coupling reagents, such as EDAC / HOBT, PyBOR, HATU, or DEPBT, in a solvent such as THF. , DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as N-methimorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine. Each R_z is independently -L_AND'-M'-R_D (for example, —L_AND- N (Rb ") C (O) -L_s-R_and), and D, L₃, Ri, R₂, Rs, L_AND, Rb ”, Ls, Re&gt; L_AND', M' and Rd are as defined above. Alternatively, the TR functionality_D can be similarly introduced after removal of the Boc protecting groups in V to produce

<img file="MX346264B_D0807.tif" />

295 the compounds of Formula VII.

<img file="MX346264B_D0808.tif" />

R_;IMPI

INSTITUTO MEXICANO Di LA INDUSTRIAL PROPERTY

<img file="MX346264B_D0809.tif" />

R, R: N -... y _ // n

N nA ^Boc "You

<img file="MX346264B_D0810.tif" />

<img file="MX346264B_D0811.tif" />

SAW

<img file="MX346264B_D0812.tif" />

vn

REACTION SCHEME VII

As another non-limiting example, the compounds of the present invention can be prepared in accordance with the

Reaction Scheme VIII starting from the compound of Formula II,

<img file="MX346264B_D0813.tif" />

<img file="MX346264B_D0814.tif" />

296 initially cleaving the diol in the form

<img file="MX346264B_D0815.tif" />

subsequent acid hydrolysis of acetonide. This intermediate dialdehyde is then treated with an aryl boronate or arylboronic acid (compound IV in which A and Y are as described above, or compound Vil) and aniline III (in which 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._shalogen. Alternatively, Formula VIII can be deprotonated with a strong base (e.g. sodium hydride) and alkylated with R_s-halogen as well, followed by acid hydrolysis of the phenol protecting groups. Sulfonylation of 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. The boronate of Formula X is produced by heating Formula IX with bis (pinacholate) diboron in the presence of X-fos and a palladium catalyst, such as Pd₂(dba)₃ and a base such as potassium acetate in an organic solvent such as dioxane. Formula X is also derivatized to the final product by heating an appropriately substituted heteroaryl halide in the presence of a palladium catalyst such as PdCI₂(dppf) in the presence of a base such as sodium carbonate in a mixture of toluene and ethanol. R_s

<img file="MX346264B_D0816.tif" />

297 it is as defined above.

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MEXICAN INSTITUTE

DE LA MOHEDAL · INDUSTRIAL

<img file="MX346264B_D0817.tif" />

(DJ

Reaction Scheme VIII can be replaced with X in which D is defined above, and such compounds can be easily prepared according to the procedure described in Reaction Scheme VIII.

<img file="MX346264B_D0818.tif" />

NaH

R_s-Hallogen

THF / DMF

<img file="MX346264B_D0819.tif" />

<img file="MX346264B_D0820.tif" />

I. NaH R_s-Hallogen THF / DMF

2. H +

3. C. FgSOgF KjCOj, DMF δ

<img file="MX346264B_D0821.tif" />

<img file="MX346264B_D0822.tif" />

X-Phos. Pd2 (dba) 3 KOAc, dioxane Δ

<img file="MX346264B_D0823.tif" />

Y-Br, Pd °

NagCOg toluene / EtOH 1: 1

Δ

<img file="MX346264B_D0824.tif" />

REACTION SCHEME VIII

<img file="MX346264B_D0825.tif" />

298

Even as another non-limiting example, the compounds

IMPI

INSTITUTO MEXICANO DE LA FROFIEDAD INDUSTRIAL of the present invention can be prepared in accordance with the

Reaction Scheme IX starting from the compounds of Formula II and Formula III. The carboxylic acid of Formula III is activated towards coupling using reagents such as isobutyl chloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as di-isopropylethylamine. After activation, the 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 produce the compound of Formula IV. The benzimidazole of Formula IV is treated with SEM-CI in the presence of a base in an aprotic solvent such as THF, yielding two V-protected benzimidazole regioisomers. Boronate VI esters are produced by heating Formula V with bis (pinacholate) diboron in the presence of a palladium catalyst, such as PdCI₂(dppf), X-Fos, and a base such as potassium acetate in an organic solvent such as dioxane. Heating produces both regioisomers of benzimidazole VI. The Vil diol is cut oxidatively followed by subsequent acid hydrolysis of the acetonide. This intermediate aldehyde is then treated with an aryl boronate VI and aniline VIII (in which 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, butyllithium, or potassium hydride,

299 IMPIAS

MEXICAN INSTITUTE

DE LA FOFIEDAD followed by alkylation with R_s-halogen, followed by acid hydrolysis of the protecting groups pyrrolidine and benzimidazole, preferably by treatment with mineral acid, such as hydrochloric acid in an alcoholic solvent such as methanol. Carboxylic acid R_zCOOH is activated towards coupling using reagents such as isobutyl chloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as di-isopropylethylamine. After activation, Formula X is added to the reaction, with isolation

W

Q of Formula XI. in each Formula within the Scheme of (^D )

Reaction IX can be replaced with "2". in which D is defined above, and said compounds can be easily prepared according to the procedure described in the Scheme of

Reaction IX.

300

<img file="MX346264B_D0826.tif" />

<img file="MX346264B_D0827.tif" />

<img file="MX346264B_D0828.tif" />

<img file="MX346264B_D0829.tif" />

Br

<img file="MX346264B_D0830.tif" />

NH₂ nh₂

1) HATU

DIPEA DMSO

Br

SEM-CI NaH THF

2)

HOAc 60 ° C

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL FROMEDAD

62% Global (both regioisomers)

IV

III

2. HCI, MeOH

PingBj PdCI₂(dppf) KOAc Dioxane 90^QC. 1 h

1. NaH R $ -Halogen THF / DMF

<img file="MX346264B_D0831.tif" />

HO

VIII

VII (both regioisomers)

Λ * W

Á OH HO OH HO (3 regioisomers) IX

W

<img file="MX346264B_D0832.tif" />

HEY YOU,

ORs

X w

<img file="MX346264B_D0833.tif" />

Rs #

ORs

XI

REACTION SCHEME IX

Some compounds of the invention of the general Formula (8), in which R₂₀ is -L_s'-M'-L_s"-Rd and D is as described above, they can be prepared according to the methods of Reaction Scheme X. Bromoalkyl ketone (1) can be reacted with an arylalkyl ketone (2) using Lewis acid mediated conditions, described above in Reaction Scheme II, to produce the diaryldketone (3). The diketone (3) can be converted to the bisboronate (4) by reaction with bis (pinacholate) diborane in the presence of a base such as potassium acetate, a catalyst such as PdCI₂(dppf) -CH₂CI₂,

3οι IMPIAS

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL · in a solvent such as DMSO, dimethoxyethane or dioxane with heating between 60-100 ° C. Bisboronate (4) can be converted to intermediate (5) by Suzuki reaction using, analogously, the Suzuki conditions described in Reaction Scheme VII. Intermediate (5) can be converted to (6) by reaction with a D-NH amine₂ under the analogous conditions described in Reaction Scheme VI. For example, the 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 to 110 ° C can provide the intermediates of the general structure (6). Compounds (6) can be converted to compounds of general Formulas (7) and then (8) using, analogously, the methods described in Reaction Scheme VII. Alternatively, the TR functionality_D it can be introduced in a similar manner to the compounds of Formula (7) to produce the compounds of Formula (X-1).

<img file="MX346264B_D0834.tif" />

(7)

<img file="MX346264B_D0835.tif" />

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INDUSTRIAL

302

HN — 7, d - NH

I ¿U / V ---^------ · N \ N \ a N \ / —nn— y _-- oi — l o ----. ' ,&gt; ', s

R20R (8)

<img file="MX346264B_D0836.tif" />

REACTION SCHEME X

Intermediates (6) can also be prepared using the route shown in Reaction Scheme XI. Intermediate (3) can be reacted with a D-NH amine₂using, in an analogous way, the conditions described in Reaction Schemes VI and X to provide the intermediates (9), which can be converted into (10) using, in an analogous way, the conditions as previously described in Scheme of Reaction X; and (10), in turn, can be converted to compounds (6) using the Suzuki reaction conditions described in Reaction Scheme VII.

D y— O DO — ν '"

I r ^ V-Br, Β-Χ ^ I

P) ----- i. Κ / Ν ^ ,. 4 / ---- Ό \ 1⁰ --- * (6) i! Saw^x--‘

·. ..V 'i- .. / (9) (10)

REACTION SCHEME XI

303

<img file="MX346264B_D0837.tif" />

Even as another non-limiting example, the compounds

IMPI

INSTITUTO MEXICANO Dt LA MONEDAD INDUSTRIAL of the invention of the General Formula (15), in which R₂₀ is -L_s'-M'Ls ”-Rd and D is as described above, they can be prepared as shown in Reaction Scheme XII. A 1,4-diketone compound (3) can be reacted with an amine D-NH₂, under acid catalazid conditions, such as acetic acid, TFA, formic acid or HCl, to produce compounds (11). For 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 a temperature between about 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 about 70 ° C to provide compounds (11). Amines that can be reacted in accordance with the above description include, but are not limited to, those amines described or mentioned in Reaction 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, the reaction of compounds (11) (1 equivalent) with iron powder (approximately 6 equivalents) in the presence of ammonium chloride (approximately 3 equivalents) in a solvent mixture of ethanol: THF: water (1: 1 : 0.25) at reflux can supply the compounds

<img file="MX346264B_D0838.tif" />

304

IMPI

INSTITUTO MEXICANO Dt LA PROHS »AD INDUSTRIAL (12). The conversion of (11) to (12) can also be effected by other methods described above in Reaction Scheme II to convert Vil 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 the

Reaction Scheme II, for example using EDAC / HOBt (2 equivalents) and an appropriate acid in solvents such as DMF at about room temperature. Compounds (13) can be converted to compounds (14) using TFA / CH₂CI₂ as described above to convert IX to X in the Scheme of

Reaction II. Compounds (14) can be converted to compounds (15) using procedures analogous to those in Reaction Scheme II to convert X to XI, such as the coupling procedure to convert (12) to (13). Alternatively, the TR functionality_D It can be introduced in a similar manner to the compounds of Formula (14) to produce the compounds of Formula (XII-1).

<img file="MX346264B_D0839.tif" />

(B)

<img file="MX346264B_D0840.tif" />

305

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INSTITUTO M1XJCAN · M la nonsoA »INDUSTRIAL

<img file="MX346264B_D0841.tif" />

(14) (15)

<img file="MX346264B_D0842.tif" />

(ΧΠ-1)

REACTION SCHEME XII

Compounds of general Formula (19), in which D is as described above, can be prepared according to the methods of Reaction Scheme XIII. Compounds of general Formula (16) can be converted to compounds of general Formula (17) using a Buchwald reaction with tert-butyl-2-carbamoylpyrrolidine-1-carboxylate. This Buchwald reaction can be carried out in the presence of a base (for example, cesium carbonate), a palladium catalyst (for example, tris (dibenzylideneacetone) d¡palladium (0)), a phosphine ligand (for example, 4 , 5-bis (diphenylphosphino) -9,9-dimethylxanthene) in a solvent such as dioxane with heating to about 80-120 ° C. Intermediate (17) can be reduced to (18) and cyclized to (19) using, analogously, the conditions generally described in Reaction Scheme IV. Compounds (19) can be further reacted as illustrated in

306

<img file="MX346264B_D0843.tif" />

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Reaction Scheme

IV to provide the compounds of the invention. Each phenyl ring in the above structures can be substituted with X₁₃, in which X₁₃ is H, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy. The cis and trans stereoisomeric pyrrolidine mixtures in the Reaction Scheme

XIII can be separated into the cis and trans isomers using standard chromatography techniques.

<img file="MX346264B_D0844.tif" />

REACTION SCHEME XIII

Some compounds of the invention of the general Formula (23), in which D is as described above, can be prepared according to the methods of Reaction Scheme XIV. Compounds (16) can be reacted with compound (20) using a Buchwald reaction as generally described in Reaction Scheme XIII to provide compounds (21). Compounds (21) can be reduced to compounds (22) and cyclized to (23) using, analogously, the conditions generally described in

IMPI msi i ru iu Mexican of the industrial currency

<img file="MX346264B_D0845.tif" />

307

Previous Reaction Schemes.

(16) +

NH₂

Λ-ό

-V

NHCOsMe (20)

NHCO₂Me / γ- ° „-Ñ O