RU2771875C2 - Heterocyclic inhibitors of mct4 - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula VII, where the values W, Y, L, n are defined in the claims.

EFFECT: compounds are useful in the treatment of MCT4 mediated diseases such as proliferative and inflammatory diseases.

12 cl, 30 tbl, 269 ex

Description

This application claims priority over United States Provisional Application No. 62/433113, filed December 12, 2016, the contents of which are incorporated by reference as if written herein in its entirety.

This document discloses new heterocyclic compounds and compositions and their use as pharmaceuticals for the treatment of disease. Also provided are methods for suppressing MCT4 activity in a human or animal subject for the treatment of diseases such as cancer.

The excretion of lactic acid from glycolytic cells is usually mediated by the monocarboxylate transporter MCT4. MCT4 exhibits a low affinity for lactate (K _m =28 mM) associated with a high metabolic rate, allowing for rapid excretion of large amounts of lactic acid. MCT4 expression is usually limited to highly glycolytic tissues such as white muscle fibers, lymphocytes, astrocytes, and Sertoli cells. Although MCT4 is absent in most normal tissues, MCT4 expression is highly elevated and correlates with poor survival in multiple cancer indications, including colorectal cancer, glioma, head and neck cancer, triple-negative breast cancer, and prostate cancer. , KRAS mutant lung cancer, liver cancer, and kidney cancer.

The correlation of MCT4 expression and poor cancer outcome appears to be a significant functional consequence in a variety of cancer models. Stable expression of MCT4 is highly oncogenic in a xenograft model of Ras-transformed respiratory-impaired fibroblasts. In contrast, MCT4 silencing provides slowing or elimination of tumor growth in xenograft models of breast cancer, colorectal cancer, and glioma. MCT4 expression is required for inflammatory cytokine IL-8 mediated angiogenesis in xenograft models of breast and colon cancer. MCT4 has also been shown to play important roles in cancer cell migration, invasion, and various aspects of the Warburg effect (eg, proliferation on glucose, extracellular oxidation, and lactate secretion).

Suppression of MCT4-mediated lactic acid clearance may represent an effective strategy for disrupting the Warburg effect in cancer. Unfortunately, effective and selective MCT4 inhibitors have not been described. Moderate to weak inhibitors of MCT4 are known (eg, phloretin and α-CN-4-OH-cinnamate); however, such compounds randomly repress a number of other transporters, including MCT1.

Thus, there is a need for effective and selective MCT4 inhibitors for use in the treatment or prevention of cancer.

DETAILED DESCRIPTION

New compounds and pharmaceutical compositions have been discovered, some of which have been found to inhibit MCT4, along with methods of synthesis and use of the compounds, including methods of treating MCT4 mediated diseases in a patient by administering the compounds.

A compound of structural formula I is provided

or its salt, where

A ¹ , A ² and A ³ are independently selected from N and C, where at least one of A ¹ , A ² and A ³ is N;

L is selected from bond, methylene and ethylene;

W selected from

X is H or absent or selected from alkenylamino, alkyl, aminoalkenyl and aminoalkyl, any of which is optionally substituted with one to three R ¹ groups;

Y is selected from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl, and heteroaryl, any of which is optionally substituted with one to three R ² groups, or

X and Y together with the atoms to which they are attached may form an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring, any of which is optionally substituted with one to three R ⁷ groups; and

Z is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ¹ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, heteroaryl;

each R ² is independently selected from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or

two R ² together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is optionally substituted with one to three R ⁸ groups, or

two R ³ together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₆ alkyl, where R ⁴ and R ⁵ together contain no more than 6 carbon atoms, or

R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R ⁶ is selected from H and C ₁ -C ₄ alkyl;

each R ⁷ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

Certain compounds disclosed herein may have useful MCT4 inhibitory activity and may be useful in the treatment or prevention of a disease or condition in which MCT4 plays an active role. Thus, in broad terms, certain embodiments also provide pharmaceutical compositions comprising one or more of the compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for making and using the compounds and compositions. Certain embodiments provide methods for suppressing MCT4. Other embodiments provide methods for treating an MCT4 mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition of the present invention. Also contemplated is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by suppression of MCT4.

In some embodiments, X is selected from alkenylamino, alkyl, aminoalkenyl, aminoalkyl, and H; and Y is selected from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl.

In some embodiments, X and Y, together with the atoms to which they are attached, may form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring.

In some embodiments, exactly two of A ¹ , A ² and A ³ are N.

In some embodiments, exactly one of A ¹ , A ² and A ³ is N.

In some embodiments, A ¹ and A ² are C; and A ³ is N.

In some embodiments, X is hydrogen.

.In some embodiments, W is selected from

.

In some embodiments, W is selected from

In some embodiments, W is

In some embodiments, Y is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ² groups.

In some embodiments, Y is selected from phenyl, thienyl, thiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, indazolyl, and indolyl.

In some embodiments, Y is selected from quinolinyl, isoquinolinyl, cinnolinyl, indazolyl, and indolyl.

In some embodiments, Y is selected from phenyl, thienyl, and thiazolyl.

In some embodiments, Z is selected from phenyl, pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, indazolyl, and indolyl.

In some embodiments, Z is selected from phenyl and pyridinyl.

In some embodiments, each R ² is independently selected from alkenyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments, each R ² is independently selected from alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halogen, and haloalkyl.

In some embodiments, the two R ² together with intermediate atoms form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

In some embodiments, each R ³ is independently selected from alkenyl, alkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments, each R ³ is independently selected from alkoxy, alkyl, aryl, and heteroaryl.

In some embodiments, the two R ³ together with intermediate atoms form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

In some embodiments, each R ³ is alkoxy.

In some embodiments, each R ³ is methoxy.

In some embodiments, each R ³ is halo.

In some embodiments, each R ³ is independently selected from F, Br, and I.

In some embodiments, each R ³ is F.

In some embodiments, R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₂ alkyl.

In some embodiments, R ⁴ and R ⁵ are independently selected from H and methyl.

In some embodiments, R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

In some embodiments, R ⁶ is selected from H and C ₁ -C ₂ alkyl.

In some embodiments, R ⁶ is selected from H and methyl.

In some embodiments, each R ⁷ is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.

In some embodiments, each R ⁷ is independently selected from alkyl and alkoxy.

In some embodiments, the compounds are characterized by structural formula Ia:

or its corresponding salt or tautomer, where

A ⁵ is selected from C-X and N;

And ⁶ is selected from CY and N;

and A ⁷ and A ⁸ are selected from the following combinations:

A ⁷ is C and A ⁸ is NH; or

A ⁷ is N and A ⁸ is N;

where at least one of A ⁵ , A ⁶ and A ⁷ is N;

L is selected from bond and methylene;

W selected from

X is H or selected from alkenylamino, alkyl, aminoalkenyl and aminoalkyl, any of which is optionally substituted with one to three R ¹ groups;

Y is selected from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which is optionally substituted with one to three R ² groups, or

X and Y together with the atoms to which they are attached may form an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring, any of which is optionally substituted with one to three R ⁷ groups; and

Z is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ¹ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, heteroaryl;

each R ² is independently selected from alkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl;

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl;

R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₆ alkyl, where R ⁴ and R ⁵ together contain no more than 6 carbon atoms;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

each R ⁷ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.

In some embodiments, the compounds are characterized by structural formula II:

or its corresponding salt, where

L is selected from bond and methylene;

W selected from

Y is selected from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl and heteroaryl, any of which is optionally substituted with one to three R ² groups;

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ² is independently selected from alkyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or

two R ² together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

each R ³ is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is optionally substituted with one to three R ⁸ groups, or

two R ³ together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₆ alkyl, where R ⁴ and R ⁵ together contain no more than 6 carbon atoms, and where at least one of R ⁴ and R ⁵ is C ₁ -C ₆ alkyl, or

R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

In some embodiments of structural formula II

L is a bond; and

each R ² is selected from alkenyl, C ₂ -C ₆ alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments of structural formula II

Z is selected from aryl and heteroaryl, either of which is substituted with one to three R ³ groups;

each R ² is selected from alkenyl, C ₂ -C ₆ alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, heteroaryl, and haloalkyl; and

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, cycloalkyl, aryl, and heteroaryl.

In some embodiments of structural formula II

Y is heteroaryl and is substituted with one to three R ² groups; and

each R ² is selected from alkenyl, C ₂ -C ₆ alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments of structural formula II

Y is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl and oxazolyl, any of which is substituted with one to three R ² groups; and

each R ² is selected from alkenyl, C ₂ -C ₆ alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments of structural formula II, at least one of R ⁴ and R ⁵ is H.

In some embodiments of structural formula II, exactly one of R ⁴ and R ⁵ is H.

In some embodiments, the compounds are characterized by structural formula III:

or its corresponding salt, where

L is selected from bond and methylene;

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one or two R ³ groups;

R ^2a and R ^2b are independently selected from H, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, halo, cycloalkyl, and heterocycloalkyl;

each R ³ is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, amino, aminoalkyl, carboxamido, halogen, cyano, hydroxy, and cycloalkyl, and is optionally substituted with one or two R ⁸ groups;

R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₆ alkyl, where R ⁴ and R ⁵ together contain no more than 6 carbon atoms, and where at least one of R ⁴ and R ⁵ is C ₁ -C ₆ alkyl, or

R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R ⁶ is selected from H and methyl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

In some embodiments of structural formula III

Z is selected from quinolinyl, isoquinolinyl, cinnolinyl, indazolyl and indolyl, any of which is optionally substituted with one to three R ³ groups; and

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.

In some embodiments of structural formula III, Z is selected from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one to three R ³ groups.

In some embodiments of structural formula III, R ² is selected from alkenyl, C ₂ -C ₆ alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halogen, heteroaryl, and haloalkyl.

In some embodiments of structural formula III, R ² is selected from alkoxy, alkyl, halogen, haloalkyl, and haloalkoxy.

In some embodiments of structural formula III, each R ³ is independently selected from alkenyl, alkoxy, alkyl, amino, aryl, halogen, heteroaryl, and haloalkyl; and

In some embodiments of structural formula III, Z is selected from alkyl, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one to three R ³ groups.

In some embodiments of structural formula III

L is a bond;

Z is selected from aryl and heteroaryl, either of which is substituted with one to three R ³ groups; and

each R ³ is independently selected from alkenyl, alkoxy, alkyl, amino, fluorine, bromine and iodine.

In some embodiments of structural formula III

L is methylene;

Z is selected from aryl and heteroaryl, either of which is substituted with one to three R ³ groups; and

each R ³ is independently selected from alkenyl, C ₂ -C ₆ alkoxy, C ₄ -C ₈ alkyl, aryl, and iodine.

In some embodiments of structural formula III

L is a bond; and

Z is selected from pyridin-3-yl and pyridin-4-yl and is optionally substituted with one to three R ³ groups.

In some embodiments of structural formula III

L is methylene; and

Z is pyridyl and is optionally substituted with one to three R ³ groups.

In some embodiments of structural formula III

L is methylene; and

Z is pyridyl and is optionally substituted with two or three R ³ groups.

In some embodiments, the compounds are characterized by structural formula IV:

or its corresponding salt, where

L is selected from bond and methylene;

W selected from

Z is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl;

R ⁴ and R ⁵ are independently selected from H and C ₁ -C ₆ alkyl, where R ⁴ and R ⁵ together contain no more than 6 carbon atoms;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

n is selected from 1, 2 and 3.

In some embodiments, the compounds are characterized by the structural formula V:

or its corresponding salt, where

L is selected from bond and methylene;

Y is selected from phenyl, thienyl, furyl, thiazolyl and oxazolyl, any of which is optionally substituted with one or two R ² groups, or

each R ² is independently selected from alkoxy, alkylthio, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, and halogen;

R ^3a is selected from H, alkoxy, haloalkoxy, cycloalkoxy, amino and halogen;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl, or

R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and

R ⁶ is selected from H and C ₁ -C ₄ alkyl.

In some embodiments, the compounds are characterized by structural formula VI:

or its corresponding salt, where

L is selected from bond and methylene;

R ^2a is selected from alkoxy, alkylthio, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy and halogen;

R ^3a is selected from H, alkoxy, haloalkoxy, cycloalkoxy, amino and halogen;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl, or

R ⁴ and R ⁵ together with the atoms to which they are attached form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and

R ⁶ is selected from H and C ₁ -C ₄ alkyl.

In some embodiments, the compounds are characterized by structural formula VII:

or its corresponding salt, where

Y is selected from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl, and heteroaryl, any of which is optionally substituted with one to three R ² groups, or

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ² is independently selected from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or

two R ² together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

each R ³ is independently selected from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is optionally substituted with one to three R ⁸ groups, or

two R ³ together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₆ alkyl, where exactly one of R ⁴ and R ⁵ is methyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

In some embodiments, the compounds are characterized by structural formula VII:

or its corresponding salt, where

L is selected from bond and methylene;

W selected from

Y is selected from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl, and heteroaryl, any of which is optionally substituted with one to three R ² groups;

each R ² is independently selected from alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl);

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and

R ⁶ is selected from H and C ₁ -C ₄ alkyl.

In some embodiments of structural formula VII, Y is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ² groups.

In some embodiments of structural formula VII, each R ² is independently selected from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halogen, and haloalkyl.

In some embodiments of structural formula VII, W is

In some embodiments of structural formula VII, n is 1 to form azetidin-1-yl.

In some embodiments of structural formula VII, L is a bond.

In some embodiments, the compounds are characterized by structural formula VIII:

or its corresponding salt, where

L is selected from bond and methylene;

Y is selected from phenyl, indazolyl, thienyl, indazolyl and indolyl, any of which is optionally substituted with one or two R ² groups;

n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl);

each R ² is independently selected from alkyl, alkoxy, alkylthio, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, and halogen;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and

R ⁶ is selected from H and C ₁ -C ₄ alkyl.

In some embodiments of structural formula VIII, Y is selected from phenyl and indazolyl, any of which is optionally substituted with one or two R ² groups.

In some embodiments of structural formula VIII, each R ² is independently selected from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halogen, and haloalkyl.

In some embodiments of structural formula VIII, n is 1 to form azetidin-1-yl.

In some embodiments of structural formula VIII, L is a bond.

In some embodiments of structural formula VIII, Y is phenyl substituted with one or two R ² groups independently selected from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo, and haloalkyl.

In some embodiments of structural formula VIII, each R ² is independently selected from C ₁ -C ₄ alkoxy, cyclopropoxy, cyclobutoxy, and C ₁ -C ₃ alkyl.

In some embodiments of structural formula VIII, Y is indazolyl substituted with R ² groups selected from methyl, ethyl, and propyl.

In some embodiments of structural formula VIII, Y is selected from

R ^{2c is} selected from C ₁ -C ₄ alkoxy and C ₁ -C ₄ cycloalkoxy;

R ^2d is absent or selected from C ₁ -C ₄ alkoxy; and

R ^2e is C ₁ -C ₄ alkyl.

In some embodiments, the compounds are characterized by structural formula IX:

or its corresponding salt, where

L is selected from bond and methylene;

W selected from

Y is selected from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl and heteroaryl, any of which is optionally substituted with one to three R ² groups;

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ² is independently selected from alkyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and

R ⁶ is selected from H and C ₁ -C ₄ alkyl.

In some embodiments of structural formula IX, Y is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ² groups.

In some embodiments of structural formula IX, each R ² is independently selected from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halogen, and haloalkyl.

In some embodiments of structural formula IX, W is

In some embodiments of structural formula IX, L is a bond.

In some embodiments of structural formula IX, Y is phenyl substituted with one or two R ² groups independently selected from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halogen, and haloalkyl.

In some embodiments of structural formula IX, each R ² is independently selected from C ₁ -C ₄ alkoxy, cyclopropoxy, cyclobutoxy, and C ₁ -C ₃ alkyl.

In some embodiments, the compounds are characterized by the structural formula X:

or its corresponding salt, where

W selected from

R ^2e is C ₁ -C ₄ alkyl;

L is selected from bond and methylene;

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ³ is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is optionally substituted with one to three R ⁸ groups, or

two R ³ together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

In some embodiments of the structural formula, XW is

In some embodiments of the structural formula X L is a bond.

In some embodiments of the structural formula XZ is selected from phenyl and indazolyl, any of which is optionally substituted with one to three R ³ groups.

In some embodiments of the structural formula X Z is selected from

n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl);

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

R ⁹ is selected from halogen, amino and C ₁ -C ₄ alkoxy.

In some embodiments of the structural formula XR ⁹ is selected from chlorine, dimethylamino and ethoxy.

In some embodiments of the structural formula XR ⁹ is selected from chlorine and ethoxy.

In some embodiments of the structural formula, X n is 1 to form azetidin-1-yl.

In some embodiments, the compounds are characterized by structural formula XI:

or its corresponding salt, where

W selected from

n is 1, 2 or 3 (to form cyclopropyl, cyclobutyl or cyclopentyl);

L is selected from bond and methylene;

Z is selected from aryl and heteroaryl, any of which is optionally substituted with one to three R ³ groups;

each R ³ is independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido, halogen, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and is optionally substituted with one to three R ⁸ groups, or

two R ³ together with intermediate atoms form a 5-7-membered cycloalkyl or heterocycloalkyl ring;

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

each R ⁸ is independently selected from cyano, halo, hydroxy and oxo.

In some embodiments of structural formula XI, W is

In some embodiments of structural formula XI, L is a bond.

In some embodiments of structural formula XI, Z is selected from phenyl and indazolyl, any of which is optionally substituted with one to three R ³ groups.

In some embodiments of the structural formula XI Z is selected from

n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl);

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

R ⁹ is selected from halogen, amino and C ₁ -C ₄ alkoxy.

In some embodiments of structural formula XI, R ⁹ is selected from chlorine, dimethylamino, and ethoxy.

In some embodiments of structural formula XI, R ⁹ is selected from chlorine and ethoxy.

In some embodiments of structural formula XI, n is 1 to form azetidin-1-yl.

In some embodiments, the compounds are characterized by structural formula II:

or its corresponding salt, where

L is selected from bond and methylene;

W selected from

Y is selected from

R ^2e is C ₁ -C ₄ alkyl;

Z is selected from

n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl);

R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl;

R ⁶ is selected from H and C ₁ -C ₄ alkyl; and

R ⁹ is selected from halogen and C ₁ -C ₄ alkoxy.

In some embodiments of structural formula II, W is

In some embodiments of structural formula II, R ⁹ is selected from chlorine and ethoxy.

In some embodiments of structural formula II, L is a bond.

In some embodiments of structural formula II

Y represents

R ^{2c is} selected from C ₁ -C ₄ alkoxy and C ₁ -C ₄ cycloalkoxy; and

R ^2d is absent or selected from C ₁ -C ₄ alkoxy.

In some embodiments of structural formula II

R ^2c is selected from methoxy, methylpropoxy, cyclopropoxy and cyclobutoxy; and

R ^2d is absent or selected from methoxy.

In some embodiments of structural formula II

иY represents

and

R ^2e is C ₁ -C ₄ alkyl.

In some embodiments of structural formula II, R ^2e is selected from ethyl and propyl.

In some embodiments of structural formula II, Z is

In some embodiments of structural formula II, n is 1 to form azetidin-1-yl.

In some embodiments of structural formula II, Z is

In some embodiments of structural formula II, Z is

In some embodiments of structural formula II, R ⁹ is selected from chlorine and ethoxy.

Embodiments are also contemplated where any embodiment presented above may be combined with any one or more of such embodiments, provided that the combination is not mutually exclusive.

As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment where two groups are combined to form a cycloalkyl is mutually exclusive with an embodiment where one group is ethyl and the other group is hydrogen. Similarly, an embodiment where one group is CH2 is mutually exclusive with an embodiment where the same group is NH.

Also provided is a compound selected from the examples disclosed herein.

The present invention also relates to a method for inhibiting at least one function of MCT4, comprising the step of bringing MCT4 into contact with a compound described herein. Cell phenotype, cell proliferation, MCT4 activity, change in biochemical yield obtained by active MCT4, expression of MCT4, or binding of MCT4 to a natural binding partner can be controlled. Such methods may be methods of treating a disease, biological assays, cellular assays, biochemical assays, or the like.

Also provided herein is a method for treating an MCT4 mediated disease comprising administering a therapeutically effective amount of a compound disclosed herein, or a salt thereof, to a patient in need thereof.

In some embodiments, the disease is selected from proliferative inflammatory diseases.

In some embodiments, the disease is a metabolic disease.

In some embodiments, said metabolic disease is selected from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholic steatohepatitis, obesity, and insulin resistance.

In some embodiments, said diabetes is type II diabetes.

In some embodiments, said dyslipidemia is hyperlipidemia.

Further provided is a method for achieving an effect in a patient, comprising administering a therapeutically effective amount of a compound disclosed above to the patient, wherein the effect is selected from the group consisting of lowering triglycerides, lowering cholesterol, and lowering hemoglobin A1c.

Additionally provided is the method disclosed above, wherein said cholesterol is selected from LDL and VLDL cholesterol.

Further provided is the method disclosed above, wherein said triglycerides are selected from blood plasma triglycerides and liver triglycerides.

Also provided herein is a compound disclosed herein for use as a drug.

Also provided herein is a compound disclosed herein for use as a drug for the treatment of a disease mediated by MCT4.

Also contemplated is the use of the compound disclosed herein as a drug.

Also contemplated is the use of a compound disclosed herein as a drug for the treatment of a disease mediated by MCT4.

Also provided is a compound disclosed herein for use in the manufacture of a medicament for the treatment of a disease mediated by MCT4.

Also contemplated is the use of a compound disclosed herein for the treatment of a disease mediated by MCT4.

Also provided herein is a method for inhibiting MCT4, which involves bringing MCT4 into contact with a compound disclosed herein, or a salt thereof.

Also provided herein is a method for achieving an effect in a patient, comprising administering a therapeutically effective amount of a compound disclosed herein, or a salt thereof, to a patient, wherein the effect is selected from cognitive enhancement.

In some embodiments, the MCT4 mediated disease is selected from proliferative inflammatory diseases.

Also provided is a method for modulating MCT4 mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

Also provided is a pharmaceutical composition containing a compound disclosed herein together with a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated for oral administration.

In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule.

Abbreviations and definitions

In order to facilitate understanding of the present invention, a number of terms and abbreviations used in this document are defined below as follows.

When introducing elements according to the present invention or its preferred embodiment(s), the singular noun form and "specified" are intended to denote one or more elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term "and/or" when used in a list of two or more items means that any one of the listed items may be used alone or in combination with any one or more of the listed items. For example, the expression "A and/or B" is intended to mean either or both of A and B, ie. A alone, B alone, or A and B in combination. The expression "A, B and/or C" is meant to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

When disclosing ranges of values and using the designation "n ₁ -n ₂ " or "from n ₁ ... to n ₂ ", where n ₁ and n ₂ are numbers, unless otherwise indicated, then this designation is intended to include the numbers themselves and the range between them. This range may consist of integers or a continuous range of values and include finite values. By way of example, the "2 to 6 carbons" range is intended to include two, three, four, five, and six carbons, since carbons exist as whole units. When comparing, as an example, the range is "1 to 3 µM (micromolar)", which is intended to include 1 µM, 3 µM, and all values between any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

The term "approximately" as used herein is intended to quantify the numerical values it modifies, designating such a value as a variable within error. Unless specific margins of error are specified, such as the standard deviation from the mean, shown on a graph or in a data table, the term "approximately" should be understood to mean the range that would cover the indicated value and the range that would be included when rounded up to given figure, taking into account significant figures.

The term "acyl", used alone or in combination herein, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety in which the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH ₃ group. "Alkylcarbonyl" or "alkanoyl" groups refer to an alkyl group attached to the parent molecular moiety via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term "alkenyl", as used herein alone or in combination, refers to a straight chain or branched hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the implementation of the specified alkenyl will contain from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise indicated, the term "alkenyl" may include "alkenylene" groups.

The term "alkoxy", as used herein alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and the like.

The term "alkyl", as used herein alone or in combination, refers to a straight chain or branched alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the implementation of the specified alkyl will contain from 1 to 10 carbon atoms. In additional embodiments, the implementation of the specified alkyl will contain from 1 to 8 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. The term "alkylene", used alone or in combination herein, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene

(-CH ₂ -) and ethylene (-CH ₂ CH ₂ -). Unless otherwise indicated, the term "alkyl" may include "alkylene" groups.

The term "alkylamino" as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety via an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

The term "alkylidene", as used herein alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

The term "alkylthio", used alone or in combination herein, refers to an alkylthioether (R-S-) radical, where the term alkyl is as defined above, and where sulfur can be singly or doubly oxidized. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term "alkynyl", used alone or in combination herein, refers to a straight chain or branched hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl contains from 2 to 6 carbon atoms. In further embodiments, said alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-,

-С≡С-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise indicated, the term "alkynyl" may include "alkynylene" groups.

The terms "amido", "carboxamido", and "carbamoyl", used alone or in combination herein, refer to an amino group, as described below, attached to the parent molecular moiety via a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to the -C(O)N(RR') group with R and R' as defined herein, or as defined by the specifically numbered groups denoted "R". The term "N-amido" as used herein, alone or in combination, refers to the group RC(O)N(R')-- with R and R' as defined herein, or as defined by the specifically numbered groups denoted "R". The term "acylamino", used alone or in combination herein, embraces an acyl group attached to the parent moiety via an amino group. An example of an "acylamino-" group is acetylamino (CH ₃ C(O)NH-).

The term "amino" as used herein alone or in combination refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may optionally be replaced. In addition, R and R' may combine to form heterocycloalkyl, any of which may be optionally substituted.

The term "aryl", used herein alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, where such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthryl.

The terms "arylalkenyl" or "aralkenyl", used alone or in combination herein, refer to an aryl group attached to the parent molecular moiety via an alkenyl group.

The terms "arylalkoxy" or "aralkoxy", used alone or in combination herein, refer to an aryl group attached to the parent molecular moiety via an alkoxy group.

The terms "arylalkyl" or "aralkyl", used alone or in combination herein, refer to an aryl group attached to the parent molecular moiety via an alkyl group.

The terms "arylalkynyl" or "aralkynyl", used alone or in combination herein, refer to an aryl group attached to the parent molecular moiety via an alkynyl group.

The terms "arylalkanoyl" or "aralkanoyl" or "aroyl", used alone or in combination herein, refer to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy, used alone or in combination herein, refers to an aryl group attached to the parent molecular moiety via an oxy.

The terms "benzo" and "benz", used alone or in combination herein, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

The term "carbamate", as used herein alone or in combination, refers to a carbamic acid ester (-NHCOO-) which may be attached to the parent molecular moiety either at the nitrogen end or the acid end, and which may optionally be substituted , as defined in this document.

The term "O-carbamyl" as used herein, alone or in combination, refers to the group -OC(O)NRR' with R and R' as defined herein.

The term "N-carbamyl", as used herein alone or in combination, refers to the group ROC(O)NR'- with R and R' as defined herein.

The term "carbonyl" as used herein, when used alone, includes formyl [-C(O)H], and in combination is a -C(O)- group.

The terms "carboxyl" or "carboxy" as used herein refer to -C(O)OH or the corresponding "carboxylate" anion, such as the anion in a carboxylic acid salt. An "O-carboxy" group refers to an RC(O)O- group, where R is as defined herein. The "C-carboxy" group refers to the -C(O)OR group, where R is as defined herein.

The term "cyano", used alone or in combination herein, refers to -CN.

The terms "cycloalkyl" or, alternatively, "carbocycle", used alone or in combination herein, refer to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, where each cyclic fragment contains from 3 to 12 carbon atoms as ring members and which may optionally be a benzo-fused ring system which is optionally substituted as defined herein. In certain embodiments, the implementation of the specified cycloalkyl will contain from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. "Bicyclic" and "tricyclic" as used herein are meant to include both fused ring systems such as decahydronaphthalene, octahydronaphthalene, as well as the polycyclic (multi-center) saturated or partially unsaturated type. In general, examples of the latter type of isomer are bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

The term "ester", as used herein alone or in combination, refers to a carboxyl group connecting two carbon-linked moieties.

The term "ether" as used herein, alone or in combination, refers to an hydroxy group connecting two carbon-linked moieties.

The terms "halo" or "halogen", used alone or in combination herein, refer to fluorine, chlorine, bromine, or iodine.

The term "haloalkoxy", used alone or in combination herein, refers to a haloalkyl group attached to the parent molecular moiety via an oxygen atom.

The term "haloalkyl", as used herein alone or in combination, refers to an alkyl radical as defined above, wherein one or more hydrogen atoms have been replaced by a halogen. Monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are specifically covered. The monohaloalkyl radical, as one example, may contain an iodine, bromine, chlorine or fluorine atom in the radical. The dihalogen and polyhaloalkyl radicals may contain two or more of the same halogen atoms, or a combination of different halogen radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-) and the like.

The term "heteroalkyl", as used herein alone or in combination, refers to a stable straight or branched chain or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the specified number of carbon atoms and from one to three heteroatoms, selected of N, O and S, and wherein the N and S atoms may be optionally oxidized and the N heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any internal position of the heteroalkyl group. No more than two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.

The term "heteroaryl", as used herein alone or in combination, refers to a 3-15 membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least at least one atom selected from N, O, and S. In certain embodiments, said heteroaryl will contain from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, the implementation of the specified heteroaryl will contain from 5 to 7 atoms. The term also encompasses fused polycyclic groups where heterocyclic rings are fused to aryl rings, where heteroaryl rings are fused to other heteroaryl rings, where heteroaryl rings are fused to heterocycloalkyl rings, or where heteroaryl rings are fused to cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, изохинолил, хиноксалинил, хиназолинил, индазолил, бензотриазолил, бензодиоксолил, бензопиранил, бензоксазолил, бензоксадиазолил, бензотиазолил, бензотиадиазолил, бензофурил, бензотиенил, хромонил, кумаринил, бензопиранил, тетрагидрохинолинил, тетразолопиридазинил, тетрагидроизохинолинил, тиенопиридинил, фуропиридинил, пирролопиридинил и т.п. Illustrative tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

The terms "heterocycloalkyl" and "heterocycle", used interchangeably herein alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as ring member, where each specified heteroatom can be independently selected from nitrogen, oxygen and sulfur. In certain embodiments, said heterocycloalkyl will contain from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will contain 3 to 8 ring members in each ring. In additional embodiments, the implementation of the specified heterocycloalkyl will contain from 3 to 7 ring members in each ring. In still additional embodiments, the implementation of the specified heterocycloalkyl will contain from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides with tertiary nitrogen atoms in the ring, and carbocyclic fused and benzo-fused ring systems; in addition, both terms also include systems where the heterocyclic ring is fused to an aryl group as defined herein or to an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocyclic groups may be optionally substituted unless specifically prohibited.

The term "hydrazinyl", as used herein alone or in combination, refers to two amino groups connected via a single bond, i.e. -N-N-.

The term "hydroxy", used alone or in combination herein, refers to -OH.

The term "hydroxyalkyl", used alone or in combination herein, refers to a hydroxy group attached to the parent molecular moiety via an alkyl group.

The term "imino", used alone or in combination herein, refers to =N-.

The term "iminohydroxy", used alone or in combination herein, refers to =N(OH) and =N-O-.

The phrase "in the backbone" refers to the longest continuous or contiguous chain of carbon atoms beginning at the point of attachment of a group to compounds of any of the formulas disclosed herein.

The term "isocyanato" refers to the -NCO group.

The term "isothiocyanato" refers to the -NCS group.

The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

The term "lower", used herein alone or in combination, where not specifically defined otherwise, means containing from 1 to and including 6 carbon atoms (ie, C 1 -C 6 alkyl).

The term "lower aryl" as used herein alone or in combination means phenyl or naphthyl, any of which may be optionally substituted as provided.

The term "lower heteroaryl", as used herein alone or in combination, means either 1) a monocyclic heteroaryl containing five or six ring members, wherein one to four of said members may be heteroatoms selected from N, O, and S, or 2) bicyclic heteroaryl, where each of the fused rings contains five or six ring members containing between them from one to four heteroatoms selected from N, O and S.

The term "lower cycloalkyl", as used herein alone or in combination, means a monocyclic cycloalkyl containing three to six ring members (ie, C3-C6 cycloalkyl). The lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower heterocycloalkyl", as used herein alone or in combination, means a monocyclic heterocycloalkyl containing three to six ring members, in which one to four members may be heteroatoms selected from N, O and S (i.e. C3-C6 heterocycloalkyl). Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl and morpholinyl. The lower heterocycloalkyls may be unsaturated.

The term "lower amino", used alone or in combination herein, refers to

-NRR', where R and R' are independently selected from hydrogen and lower alkyl, any of which may be optionally substituted.

The term "mercaptyl", as used herein alone or in combination, refers to the group RS-, where R is as defined herein.

The term "nitro", used alone or in combination herein, refers to -NO2.

The terms "oxy" or "oxa", used alone or in combination herein, refer to -O-.

The term "oxo", used alone or in combination herein, refers to ═O.

The term "perhaloalkoxy" refers to an alkoxy group where all hydrogen atoms have been replaced by halogen atoms.

The term "perhaloalkyl", used alone or in combination herein, refers to an alkyl group where all hydrogen atoms have been replaced by halogen atoms.

The terms "sulfonate", "sulfonic acid", and "sulfonic", used alone or in combination herein, refer to the -SO3H group and its anion, since sulfonic acid is used in salt formation.

The term "sulfanil", used alone or in combination herein, refers to -S-.

The term "sulfinyl", used alone or in combination herein, refers to -S(O)-.

The term "sulfonyl", as used herein alone or in combination, refers to -S(O)2-

The term "N-sulfonamido" refers to the group RS(=O)2NR'- with R and R' as defined herein.

The term "S-sulfonamido" refers to the group -S(O)2NRR' with R and R' as defined herein.

The term "sulfonamido" embraces both N-sulfonamido and S-sulfonamido groups.

The terms "thia" and "thio", used alone or in combination herein, refer to the group -S- or ether, where oxygen is replaced by sulfur. Oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

The term "thiol", used alone or in combination herein, refers to the -SH group.

The term "thiocarbonyl" as used herein, when used alone, includes thioformyl -C(S)H, and in combination is a -C(S)- group.

The term "N-thiocarbamyl" refers to the group ROC(S)NR- with R and R' as defined herein.

The term "O-thiocarbamyl" refers to the group -OC(S)NRR' with R and R as defined herein.

The term "thiocyanato" refers to the -CNS group.

The term "trihalomethanesulfonamido" refers to the group X3CS(O)2NR-, where X is halogen and R is as defined herein.

The term "trihalomethanesulfonyl" refers to the group X3CS(O)2-, where X is halogen.

The term "trihalomethoxy" refers to the group X3CO-, where X is halogen.

The term "trisubstituted silyl", as used herein alone or in combination, refers to a silicone group substituted in its three free valences by the groups listed herein, as defined for substituted amino. Examples include trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl, and the like.

Any definition herein can be used in combination with any other definition to describe a complex structural group. By definition, the trailing element of any such definition is the element that is attached to the original fragment. For example, an alkylamido complex group will be an alkyl group attached to the parent molecule via an amido group, and the term alkoxyalkyl will be an alkoxy group attached to the parent molecule via an alkyl group.

When a group is defined as "null", it means that the specified group does not exist.

The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. When substituted, substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or specifically designated sets of groups alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyl ester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O) CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate and lower urea. Where structurally possible, two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring of zero to three heteroatoms, for example, to form methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (eg, -CH2CH3), fully substituted (eg, -CF2CF3), monosubstituted (eg, -CH2CH2F), or substituted at a level between fully substituted and monosubstituted (eg, -CH2CF3). Where substituents are indicated without qualification for substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is defined as "substituted", the substituted form is specifically meant. In addition, different sets of optional substituents for a particular moiety can be defined as needed; in such cases, the optional substitution will be as defined, often immediately following the phrase "optionally substituted".

The term R or the term R', occurring alone and without a numerical designation, unless otherwise indicated, refers to a fragment selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups are to be understood as being optionally substituted as defined herein. Whether the group R has a numerical designation or not, each group R, including R, R' and Rn, where n=(1, 2, 3, ... n), each substituent and each element should be understood as independent of any others regarding selection from the group. If any variable, substituent, or element (eg, aryl, heterocycle, R, etc.) occurs more than once in a formula or general structure, its definition in each occurrence is independent of the definition in every other occurrence. Those skilled in the art will also appreciate that some groups may be attached to the parent molecule, or may occupy a position in the chain of elements at either end, as written. For example, an asymmetric group such as -C(O)N(R)- may be attached to the parent moiety either via carbon or nitrogen.

Centers of asymmetry are present in the compounds disclosed herein. Such centers are designated using the symbols "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. It should be understood that the present invention covers all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and 1-isomers and mixtures thereof. Individual stereoisomers of compounds can be obtained synthetically from commercially available starting materials that contain chiral centers, or by obtaining mixtures of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers followed by separation or recrystallization, using chromatographic techniques, direct separation of enantiomers into chiral chromatographic columns or any other suitable method known from the prior art. Starting compounds with specific stereochemistry are either commercially available or can be obtained and isolated using techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis-, trans-, syn-, anti-, entgegen- (E) and zusammen- (Z) isomers, as well as their respective mixtures. In addition, the compounds may exist as tautomers; all tautomeric isomers are provided for in the present invention. In addition, the compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

The term "bond" refers to a covalent bond between two atoms or two fragments, where the atoms connected through the bond are considered part of a larger substructure. The bond may be single, double or triple unless otherwise indicated. A dotted line between two atoms in a molecule design indicates that an additional bond may or may not be present at that position.

The term "disease" as used herein is intended to be generally synonymous with and used interchangeably with the terms "disorder", "syndrome", and "condition" (i.e., medical condition) in that they all reflect an abnormal condition. of the human or animal body, or one of its parts, which impairs its normal functioning, usually manifesting itself through distinctive signs and symptoms, and resulting in a reduction in the duration or quality of life of the human or animal.

The term "combination therapy" means the administration of two or more therapeutic agents for the treatment of a therapeutic condition or disorder described in the present invention. Such administration encompasses the co-administration of such therapeutic agents virtually simultaneously, such as in one capsule containing a fixed ratio of active ingredients, or in several separate capsules for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In both cases, the treatment regimen will provide the beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.

The term "MCT4 inhibitor" is used herein to refer to a compound that exhibits an IC50 for MCT4 activity of no more than about 100 μM, and more often no more than about 50 μM, as measured by the MCT4 enzyme assay described in General outlined in this document below. The IC50 is the concentration of the inhibitor that results in a reduction in the activity of the enzyme (eg, MCT4) to a half-maximal level. It was found that some of the compounds disclosed in this document, characterized by suppression against MCT4. In some embodiments, the compounds will have an IC50 to MCT4 of no greater than about 10 μM; in additional embodiments, the compounds will have an IC50 to MCT4 of no greater than about 5 μM; in still further embodiments, the compounds will have an IC50 to MCT4 of no greater than about 1 μM; in yet further embodiments, the compounds will have an IC50 to MCT4 of no greater than about 200 nM, as measured in the MCT4 binding assay described herein.

The phrase "therapeutically effective" is intended to quantify the amount of active ingredients used in the treatment of a disease or disorder or influencing a clinical end result.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with patient tissues without undesirable toxicity, irritation and allergic response, are commensurate with a reasonable benefit/risk ratio and are effective in relation to their intended use.

As used herein, reference to "treating" a patient is intended to include prophylaxis. Treatment may also be proactive in nature, ie. it may include disease prevention. Prevention of a disease may include complete protection against the disease, such as in the case of preventing infection by a pathogen, or may include preventing the progression of the disease. For example, the prevention of a disease may not mean the complete end of any effect related to diseases at any level, but may instead mean the prevention of disease symptoms to a clinically significant or detectable level. Disease prevention can also mean preventing disease progression to the next stage of the disease.

The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs and rabbits, and domestic animals such as dogs, cats, rabbits and horses. Preferably the patient is a human.

The term "prodrug" refers to a compound that becomes more active in vivo. Some of the compounds disclosed herein may also exist as prodrugs as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003) . Prodrugs based on the compounds described herein are structurally modified forms of the compound that rapidly undergo chemical changes under physiological conditions to provide the compound. In addition, prodrugs can be converted into a compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compound when placed in a transdermal patch reservoir using a suitable enzyme or chemical. Prodrugs are often useful because in some situations they can be administered more easily than the compound or parent drug. They may, for example, be orally bioavailable while the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as prodrugs that depend on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug would be a compound that is administered as an ester ("prodrug") but is then metabolically hydrolyzed to a carboxylic acid, the active substance. Additional examples include peptidyl derivatives of the compound.

The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts that are not pharmaceutically acceptable salts may be used in the preparation and purification of the compound in question. Base addition salts may also be formed and may be pharmaceutically acceptable. For a fuller discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt" as used herein is salts or zwitterionic forms of the compounds disclosed herein that are capable of being dissolved or dispersed in water or oil and are therapeutically acceptable as defined herein. Salts may be obtained during the final isolation and purification of the compounds, or separately by reacting the corresponding compound in free base form with the appropriate acid. Exemplary acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylene sulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpopionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate) and undecanoate. Also, the base groups in the compounds disclosed herein may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl-, diethyl-, dibutyl- and diamyl sulfates; decyl-, lauryl-, myristyl- and sterile chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric, and organic acids such as oxalic, maleic, succinic and citric. Salts can also be formed by coordinating the compounds with an alkali metal or alkaline earth metal ion. Therefore, the present invention contemplates sodium, potassium, magnesium and calcium salts with the compounds disclosed herein, and the like.

Base addition salts can be obtained during the final isolation and purification of compounds by reacting the carboxyl group with a suitable base such as a metal cation hydroxide, carbonate or bicarbonate, or with ammonia or an organic primary, secondary or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine N,N'-dibenzylethylenediamine. Other illustrative organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

While it is possible to administer the compounds of the present invention as the starting chemical, it is also possible to provide them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical compositions that comprise one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier(s) must(should) be "acceptable(s)", in the sense must(should) be compatible(s) with the other ingredients of the composition and not be harmful(harmful) to its recipient. The proper composition depends on the chosen route of administration. Any well known techniques, carriers and excipients may be used as appropriate and known in the art. The pharmaceutical compositions disclosed herein may be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, encapsulating, or compressing methods.

Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intracerebral), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most appropriate path may depend, for example, on the state and impairment of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Typically, such methods include the step of bringing into association a compound of the present invention, or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate ("active ingredient") thereof, with a carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous solution or non-aqueous solution; or as an oil-in-water liquid emulsion or as a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical preparations that can be used orally include tablets, hard capsules made from gelatin, as well as soft, sealed capsules made from gelatin, and a plasticizer such as glycerol or sorbitol. Tablets can be obtained by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be obtained by compressing in a suitable machine the active ingredient in free flowing form such as powder or granules, optionally by mixing with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or have a break line and may be formulated to provide slow or controlled release of the active ingredient from them. All formulations for oral administration should be in dosages suitable for such administration. The hard capsule may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablet or dragee coatings to identify or characterize different combinations of active compound doses.

The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds, thereby allowing highly concentrated solutions to be obtained.

In addition to the formulations previously described, the compounds may also be formulated as depot formulations. These long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds can be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may be in the form of tablets, lozenges, lozenges or gels formulated in the conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

The compounds may also be formulated into rectal compositions such as suppositories or retention enemas, for example containing traditional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

Some of the compounds disclosed herein can be administered topically, ie via non-systemic administration. This includes applying a compound disclosed herein externally to the epidermis or oral cavity, and inserting such compound into the ear, eye, and nose such that the compound does not enter the bloodstream to a significant extent. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liquid ointments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w/w (by weight) of the composition. In certain embodiments, the active ingredient may comprise no more than 10% w/w. In other embodiments, it may be less than 5% w/w. In certain embodiments, the active ingredient may be from 2% w/w to 5% w/w. In other embodiments, it may be from 0.1% to 1% w/w of the formulation.

For administration by inhalation, the compounds can be conveniently delivered from an insufflator, pressurized aerosol cans, or other convenient means of aerosol delivery. Aerosol cans may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of the present invention may take the form of a dry powder formulation, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder can be administered using an inhaler or insufflator.

Preferred unit dosage formulations are formulations containing the effective dose set forth herein below, or the appropriate portion of the active ingredient thereof.

It should be understood that, in addition to the ingredients specifically mentioned above, the formulations described above may include other agents conventional in the art, taking into account the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

The compounds can be administered orally or by injection at a dose of 0.1 to 500 mg/kg per day. The dosage range for adults generally ranges from 5 mg to 2 g/day. Tablets or other dosage forms provided in discrete units may, for convenience, contain an amount of one or more compounds that are effective at that dosage or multiple of it, for example, units containing from 5 mg to 500 mg, typically from about 10 mg to 200 mg.

The amount of active ingredient that can be combined with carrier materials to form a single dosage form will vary depending on the patient being treated and the particular route of administration.

The compounds can be administered by various means, for example, orally, topically or by injection. The exact amount of compound administered to a patient will be within the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex, diets, time of administration, route of administration, rate of elimination, combination of drugs, particular the disorder being treated and the severity of the indication or condition being treated. In addition, the route of administration may vary depending on the condition and its severity.

In some instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds described herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with the parent therapeutic agent. Or, by way of example only, the therapeutic efficacy of one of the compounds described herein can be enhanced by the administration of an adjuvant (i.e., the adjuvant alone may have only minimal therapeutic benefit, but in combination with another therapeutic agent, overall the therapeutic benefit to the patient is increased). Or, by way of example only, the benefit experienced by a patient can be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit. By way of example only, in the treatment of diabetes involving the administration of one of the compounds described herein, an increase in therapeutic benefit may also result from providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall beneficial effect experienced by the patient may be simply additive for the two therapeutic agents, or the patient may experience a synergistic beneficial effect.

Thus, in another aspect, some embodiments provide methods for treating MCT4 mediated disorders in a human or animal subject in need of such treatment, comprising administering to said subject an amount of a compound disclosed herein effective to reduce the severity or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder, which is known in the art. In a related aspect, some embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of disorders mediated by MCT4.

Also provided herein is a method of treating a disorder mediated by the MCT4 monocarboxylate transporter in a subject in need thereof, comprising sequential or co-administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

In some embodiments, the therapeutic agent is a protein kinase inhibitor.

In some embodiments, the protein kinase inhibitor is selected from Aurora B, EGFR, PLK-1, CDK inhibitors.

In some embodiments, the therapeutic agent is selected from an antimetabolite, a bcr-abl inhibitor, a DNA damaging agent, an EGFR inhibitor, a microtubule stabilizing inhibitor, a mitosis blocking inhibitor, an S-phase inhibitor, and a taxane.

In some embodiments, the therapeutic agent is a DNA disruptor selected from an alkylating agent, an anthracycline, an antimetabolite agent, a crosslinker, a DNA replication inhibitor, an intercalator, a microtubule disruptor, a PARP inhibitor, a radiomimetic agent, a radiosensitizer, a strand breaker , and a topoisomerase II inhibitor.

In some embodiments, the therapeutic agent is selected from aminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib, bcg, bicalutamide, bleomycin, buserelin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cyclophosphamide, ципротерона, цитарабина, дакарбазина, дактиномицина, даунорубицина, деметоксивиридина, дихлорацетата, диенестрола, диэтилстильбэстрола, доцетаксела, доксорубицина, эпирубицина, эстрадиола, эстрамустина, этопозида, эверолимуса, эксеместана, филграстима, флударабина, флудрокортизона, фторурацила, флуоксиместерона, флутамида, гемцитабина, генистеина, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitotrexate santhrone, nilutamide, nocodazole, olaparib, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, porfimer, procarbazine, raltitrexide, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, testosterone thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine and vinorelbine.

For use in cancer and neoplastic diseases, an MCT4 inhibitor can optimally be used in conjunction with one or more of the following non-limiting examples of anticancer agents: (1) alkylating agents including, but not limited to, cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin ( ZANOSAR), busulfan (MYLERAN) and cyclophosphamide (ENDOXAN); (2) antimetabolites, including, without limitation, mercaptopurine (PIIRINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (ARA-C), gemcitabine (GEMZAR), fluorouracil (CARAC), leucovorin (FUSILEV), and methotrexate (RHEUMATREX); (3) plant alkaloids and terpenoids, including, but not limited to, vincristine (ONCOVIN), vinblastine, and paclitaxel (TAXOL); (4) topoisomerase inhibitors including, but not limited to, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), and etoposide (EPOSIN); (5) cytotoxic antibiotics including, but not limited to actinomycin D (COSMEGEN), doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE), and mitomycin (MITOSOL); (6) angiogenesis inhibitors including, but not limited to, sunitinib (SUTENT) and bevacizumab (AVASTEST); and (7) tyrosine kinase inhibitors including, but not limited to, imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), and axitinib (JNLYTA).

If the subject is suffering from or at risk of developing an inflammatory condition, the MCT4 inhibitor compound described herein is optionally used in conjunction with one or more agents or methods for treating the inflammatory condition in any combination. Therapeutic agents/treatments for treating an autoimmune and/or inflammatory condition include, without limitation, any of the following examples: (1) corticosteroids, including, without limitation, cortisone, dexamethasone, and methylprednisolone; (2) non-steroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM) , etodolac (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN), and piroxicam (FELDENE); (3) immunosuppressants, including, but not limited to, methotrexate (RHEUMATREX), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus, and cyclophosphamide (CYTOXAN); (4) CD20 blockers, including but not limited to rituximab (RITUXAN); (5) tumor necrosis factor (TNF) blockers including, but not limited to, etanercept (ENBREL), infliximab (REMICADE), and adalimumab (HUMIRA); (6) interleukin-1 receptor antagonists, including, without limitation, anakinra (KINERET); (7) interleukin-6 inhibitors, including, without limitation, tocilizumab (ACTEMRA); (8) inhibitors of interleukin-17, including without limitation AIN457; (9) Janus kinase inhibitors, including without limitation tazocytinib; and (10) syk inhibitors, including but not limited to fostamatinib.

In some embodiments, the method further comprises performing non-chemotherapeutic methods of treating cancer.

In some embodiments, the implementation of the method further includes the implementation of radiation therapy.

In some embodiments, the method further comprises performing surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

In any event, multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order, or even simultaneously. When administered simultaneously, several therapeutic agents may be presented in one single form, or in several forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be provided in multiple doses, or both agents may be provided in multiple doses. When administered non-simultaneously, the time period between multiple doses may be of any length ranging from a few minutes to four weeks.

Thus, in another aspect, some embodiments provide methods for treating MCT4 mediated disorders in a human or animal subject in need of such treatment, comprising administering to said subject an amount of a compound disclosed herein effective to reduce the severity or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder, which is known in the art. In a related aspect, some embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of disorders mediated by MCT4.

The present invention provides compounds and pharmaceutical compositions that inhibit glutaminase activity, in particular MCT4 activity, and are thus useful in the treatment or prevention of MCT4 related disorders. The compounds and pharmaceutical compositions of the present invention selectively modulate MCT4 and are thus useful in the treatment or prevention of a number of disorders associated with MCT4 and include, without limitation, proliferative and inflammatory diseases.

Accordingly, provided herein is a method for inhibiting the activity of the MCT4 monocarboxylate transporter or a mutant thereof in a biological sample, comprising the step of contacting said biological sample with a compound disclosed herein or a salt thereof.

Also provided herein is a method for inhibiting the activity of the MCT4 monocarboxylate transporter or a mutant thereof in a patient, comprising the step of administering to the patient a compound disclosed herein or a salt thereof.

Also provided herein is a method for selectively inhibiting the activity of the MCT4 monocarboxylate transporter or a mutant thereof relative to the MCT1 monocarboxylate transporter or a mutant thereof in a patient, comprising the step of administering to the patient a compound disclosed herein or a salt thereof.

In some embodiments, suppression is at least 100-fold selective for MCT4 over MCT1.

In some embodiments, the compounds and pharmaceutical compositions of the present invention may be useful in the treatment or prevention of cancer.

In some embodiments, the compounds of the present invention may be used to prevent or treat cancer, where the cancer is one or a variant of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-associated cancers (Kaposi's sarcoma and lymphoma), anal cancer, appendix cancer, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer (including extrahepatic), bladder cancer, bone cancer (including osteosarcoma and malignant fibrous histiocytoma), brain tumors (such as astrocytomas, brain and spinal cord tumors, brainstem glioma, atypical teratoid/rhabdoid tumor of the central nervous system, embryonic tumors of the central nervous system, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, tumors of the pineal gland parenchyma of intermediate differentiation, supratentory primitive neuroectodermal tumors and pineoblastoma), breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, carcinoma of unknown primary site, central nervous system (such as atypical teratoid/rhabdoid tumor, fetal tumors and lymphoma), cervical cancer, species childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, skin T-cell lymphoma (granuloma fungoides and Sezari syndrome), bile duct (extrahepatic) , ductal carcinoma in situ (DCIS), embryonic tumors (central nervous system), endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma family tumors, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer ( such an intraok malignant melanoma, retinoblastoma), fibrous histiocytoma of bone (including malignant and osteosarcoma), gallbladder cancer, gastric (gastric) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor (extracranial, extragonadal, ovarian) , gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular cancer (liver), histiocytosis, Langerhans cells, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine, pancreatic), sarcomas Kaposi, kidney (including renal cell), Langerhans cell histiocytosis, laryngeal cancer, leukemia (including acute lymphoblastic (ALL), acute myeloid (AML), chronic lymphocytic (CLL), chronic myelogenous (CML), hairy cell), lip cancer and oral cavity, liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer (non-small cell and small cellular), lymphoma (AIDS-associated, Burkitt, cutaneous T-cell (granuloma fungoides and Cesari's syndrome), Hodgkin's, non-Hodgkin's, primary central nervous system (CNS), macroglobulinemia, Waldenström, male breast cancer, malignant fibrous histiostomy of bone, and osteosarcomas, medulloblastomas, medulloepitheliomas, melanomas (including intraocular (eye)), Merkel cell carcinomas, mesothelioma (malignant), metastatic squamous cell carcinoma of the neck with a hidden primary source, median tract carcinoma involving the NUT gene, cancer of the mouth, multiple endocrine neoplasia syndromes , multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), myeloma and multiple myeloma, myeloproliferative disorders (chronic), cancer of the nasal cavity and paranasal P sinus, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, oral cavity, lip and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer (such as epithelial, germ cell tumor and tumor with low malignant potential ), pancreatic cancer (including islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, intermediate differentiation pineal parenchymal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, plasma cell neoplasms/multiple myeloma, pleuropulmonary blastoma, breast cancer during pregnancy, primary central nervous system (CNS) lymphoma, prostate cancer, colorectal cancer, renal cell carcinoma (kidney), kidney cancer anchi and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (such as tumors of the Ewing's sarcoma family, Kaposi's, soft tissue, uterus), Cesari syndrome, skin cancer (such as melanoma, Merkel cell carcinoma, non-melanoma), small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, neck squamous cell carcinoma with an occult primary source, metastatic, gastric (gastric) cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma (skin, mycosis fungoides and Cesari's syndrome), testicular cancer, throat cancer, thymoma and carcinoma of the thymus, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), with unknown primary source, atypical cancers in children, ureter and renal pelvis, transitional cell carcinoma, urethral cancer , cancer of the uterus, endometrium, uterine sarcoma, Waldenström's macroglobulinemia or Wilms tumor.

In some embodiments, the cancer to be treated is a T cell specific cancer such as T cell lymphoma and T cell lymphoblastic leukemia.

In some embodiments, the methods described herein are used to treat a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the condition is cancer in which resistance to chemotherapeutic drugs has developed. means and/or ionizing radiation.

In some embodiments, the compounds and pharmaceutical compositions of the present invention may be useful in the treatment or prevention of an inflammatory disease.

In some embodiments, the compounds of the present invention may be used to prevent or treat an inflammatory disease, wherein the inflammatory disease is one or a variant of acid-induced lung injury, acne (PAPA), acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency , aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, angina pectoris, angioedema, anhydrotic ectodermal dysplasia (for example, with immunodeficiency), ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, induced inflammation, Behcet's disease, Bell's palsy, berylliosis, Blau's syndrome, bone pain, bronchiolitis, burns, bursitis, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataract types, cerebral aneurysm, chemical stimulus-induced inflammation, chorioretinitis , chronic heart failure, chronic lung disease in immaturity, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndromes, cryptococcosis, cystic fibrosis, interleukin-1 receptor antagonist deficiency , dermatitis, dermatitis with endotoxemia, dermatomyositis, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, hl omerulonephritis, gout, gouty arthritis, graft-versus-host disease, bowel disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schonlein disease, hepatitis, hereditary intermittent fever syndrome, herpes zoster and simplex, HIV-1 , Huntington's disease, hyaline membrane syndrome, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever, hypoplastic and other types of anemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, pigment incontinence, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy , inflammatory pain caused by insect sting inflammation, iritis, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury due to parasitic infections, prevention of transplant rejection leptospirosis, Loeffler's endocarditis, lung injury, lupus, lupus nephritis, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria-deafness-amyloidosis), multiple sclerosis, muscular atrophy, muscular dystrophy, myasthenia gravis, myocarditis , mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, multisystem inflammatory disease of neonatal age (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergy-induced asthma, obesity, allergic eye diseases, optic neuritis, transplantation organs, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, intermittent fever, periodontitis, whooping cough, perineal or peritoneal endometriosis, pharyngitis and adenitis (PFAPA syndrome), induced by races inflammation, plasma cell infection, pneumonia, pneumonitis, sumac/urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychological stress disorder, pulmonary disease, pulmonary fibrosis, pulmonary hypertension, prioderma gangrenosum, pyogenic sterile arthritis, kidney disease, retinal disease, rheumatoid disease, rheumatoid arthritis, rheumatic carditis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced disease, Sjögren's syndrome, skin disease, sleep apnea, injury spinal cord, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, systemic sclerosis (scleroderma), temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated period syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, and weight loss.

Thus, in another aspect, some embodiments provide methods for treating an MCT4 monocarboxylate transporter-mediated disorder in a subject in need thereof, comprising the step of administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is a human.

In some embodiments, the MCT4 monocarboxylate transporter-mediated disorder is selected from an inflammatory disorder and a proliferative disorder.

In some embodiments, the MCT4 monocarboxylate transporter-mediated disorder is a proliferative disorder.

In some embodiments, the proliferative disorder is cancer.

In some embodiments, the cancer is selected from adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, stomach cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, colon cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell cancer lung, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer colon, sarcoma, skin cancer, spinal cord tumor, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer and Wilms tumor.

In some embodiments, the MCT4 monocarboxylate transporter-mediated disorder is an inflammatory disorder.

In some embodiments, the inflammatory disorder is selected from Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma).

Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in human therapy.

Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of an MCT4 monocarboxylate transporter-mediated disorder, for example, as disclosed in any of the above embodiments and paragraphs that relate to methods of treatment.

Also contemplated herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an MCT4 monocarboxylate transporter-mediated disorder, for example, as disclosed in any of the above embodiments and paragraphs that relate to methods. treatment.

Metabolic syndrome (also known as metabolic syndrome X) is characterized by the presence of at least three of the following symptoms: insulin resistance; abdominal fat - in men it is defined as a waist circumference of 40 inches or more, in women - 35 inches or more; high blood sugar levels - at least 110 milligrams per deciliter (mg/dL) after fasting; high triglycerides - at least 150 mg/dl in the bloodstream; low HDL - less than 40 mg / dl; prothrombotic state (for example, high levels of fibrinogen or plasminogen activator inhibitor in the blood); or blood pressure of 130/85 mm Hg. or higher. An association has been found between metabolic syndrome and other conditions such as obesity, high blood pressure, and high levels of LDL cholesterol, all of which are risk factors for cardiovascular disease. For example, an increased association has been shown between metabolic syndrome and atherosclerosis. People with metabolic syndrome are also more likely to develop type 2 diabetes, as well as PCOS (polycystic ovarian syndrome) in women and prostate cancer in men.

As described above, insulin resistance can manifest itself in several ways, including type 2 diabetes. Type 2 diabetes is the condition most clearly associated with insulin resistance. Compensatory hyperinsulinemia helps maintain normal glucose levels, often for decades, before overt diabetes develops. Eventually, pancreatic beta cells become unable to overcome insulin resistance through hypersecretion. Glucose levels rise and a diagnosis of diabetes can be made. Patients with type 2 diabetes remain hyperinsulinaemic until they develop advanced disease. As described above, insulin resistance can also be correlated with hypertension. One half of patients with significant hypertension is characterized by insulin resistance and hyperinsulinemia, and it is a fact that blood pressure is associated with the degree of insulin resistance. Hyperlipidemia is also associated with insulin resistance. The lipid profile of patients with type 2 diabetes includes elevated levels of very-low-density lipoprotein cholesterol and serum triglycerides, and sometimes elevated levels of low-density lipoprotein cholesterol. Insulin resistance has been found in people with very low HDL levels. Insulin levels have also been associated with VLDL synthesis and plasma triglyceride levels.

Accordingly, methods for treating insulin resistance in a subject are also disclosed, comprising selecting a subject in need of treatment for insulin resistance; and administering to the subject an effective amount of a compound that provides suppression of MCT4.

Specific diseases to be treated with the compounds, compositions and methods disclosed herein are diseases mediated at least in part by MCT4. Accordingly, disclosed herein are methods for reducing glycogen storage in a subject; raising HDL or HDLc levels, lowering LDL or LDLc levels, shifting LDL particle size from low density to normal LDL, lowering VLDL levels, lowering triglyceride levels, or suppressing cholesterol absorption in a subject; reducing insulin resistance, improving glucose uptake, or lowering blood pressure in a subject; reducing visceral fat in a subject; reducing serum transaminase levels in the subject; or treatment of a disease; all of which involve administering a therapeutic amount of a compound described herein to a patient in need thereof. In additional embodiments, the disease being treated may be a metabolic disease. In a further embodiment, the metabolic disease may be selected from the group consisting of obesity, diabetes mellitus, in particular type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, and hepatic steatosis. In other embodiments, the disease being treated may be selected from the group consisting of cardiovascular diseases, including vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, and peripheral vascular disease. In preferred embodiments, the above methods do not result in the induction or maintenance of a hypoglycemic state.

In addition to being useful in human therapy, some of the compounds and compositions disclosed herein may also be useful in the veterinary treatment of pets, exotic animals, and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs and cats. List of abbreviations

Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = water; Ar = aromatic group; BAST=bis(2-methoxyethyl)aminosulfur trifluoride; BCECF = 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; Bu = butyl; Bu ₃ SnH = tributyltin hydride; CD ₃ OD = deuterated methanol; CDCl ₃ = deuterated chloroform; CDI=1,1'-carbonyldiimidazole; DAST = (diethylamino)sulfur trifluoride; dba=dibenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate; DIBAL-H = diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF=N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC⋅HCl = EDCI⋅HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et = ethyl; Et ₂ O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methanamine hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-Pr = isopropyl = 2-propyl; i-PrOH = isopropanol; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; LiHMDS=lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = MeOH; MP-carbonate resin = macroporous carbonate resin based on triethylammonium-methylpolystyrene; MsCl = mesyl chloride; MTBE = methyl tert-butyl ether; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS=N-iodosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(PPh ₃ ) ₄ = tetrakis(triphenylphosphine)palladium(0); Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium(0); PdCl ₂ (PPh ₃ ) ₂ = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph=phenyl; prep-HPLC = Preparative High Performance Liquid Chromatography; PMB = para-methoxybenzyl; PMBCl = p-methoxybenzyl chloride; PMBOH = p-methoxybenzyl alcohol; PyBop = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; k.t. = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl = 1,1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS=tert-butyldiphenylsilyl; t-BuOH=tert-butanol; T3P = propylphosphonic anhydride; TEA = Et ₃ N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt=trityl=(triphenyl)methyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

General synthetic methods for the preparation of compounds

The following schemes can be used to practice the present invention.

Scheme I

In general, without being intended to be limiting, the synthetic scheme for the examples in this invention is depicted in Scheme I. A suitably substituted 2,4-diketobutanoic acid ester is reacted with a substituted hydrazine to form a pyrazole ring. Reduction of the ester results in a hydroxymethyl compound. The side chain can be completed by direct alkylation with an ester containing a halogen at the 2-position, as shown in path (a). Alternatively, the hydroxymethyl functionality is converted to a halomethyl group, which can be substituted with a 2-hydroxy ester as shown in route (b) or transformed via a Wittig chemical reaction as shown in route (c) to give an alkene.

Scheme II

Scheme II, depicted above, can be used to obtain some of the examples disclosed in this document. In step (a), the organohalide 201 is converted to organolithium, followed by condensation with a substituted acetamide to give an acetyl functionalized compound 202. This compound is reacted in step (b) under Claisen reaction conditions with an oxalic acid ester to give a 2,4-diketoester 203, which is then reacted with a substituted hydrazine in step (c) to construct the pyrazole core 204. The ester functionality is reduced in step (d), and in step (e), the resulting alcohol 205 is alkylated with the appropriate haloacetic acid ester to give ester 206. Finally, the ester is hydrolyzed in step (f) under basic conditions to give the carboxylic acid 207. In the depicted scheme, R ₁₀₀ -R ₁₀₃ will be understood by one of skill in the art to represent any suitable group. For example, in some embodiments, R ₁₀₀ and R ₁₀₁ may be independently selected from aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, any of which is optionally substituted. Similarly, in some embodiments, R ₁₀₂ and R ₁₀₃ may be independently selected from hydrogen, alkyl, and halo. R ₁₀₀ -R ₁₀₃ may also correspond to the groups defined in formulas I, II, or any other formula disclosed in this document. Finally, this scheme can be attached at any point by using the appropriate intermediate shown in this document, which is available either from commercial sources or through replacement methods of synthesis.

Scheme III

Scheme III, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Steps (a)-(d) of Scheme I are used to prepare pyrazolemethanol 301, which is then converted to bromomethyl compound 302 in step (e) using one of the various techniques available for this conversion. The alkyl halide 302 is then reacted under the Williamson ether synthesis reaction conditions with the hydroxyester in step (f) to give 303. The synthesis is then completed in step (g) by hydrolysis of the ester to give 304.

Scheme IV

Scheme IV, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Steps (a)-(d) of Scheme I are used to give pyrazolemethanol 401 which is alkylated to give tBu ester 402. Ester cleavage is carried out under acidic conditions to give acid 403.

Scheme V

Scheme V, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Steps (a)-(e) of Scheme III are used to give (bromomethyl)pyrazole 501. Reaction with the hydroxyester under basic conditions gives the tBu ester 502. Ester cleavage is carried out under acidic conditions to give acid 503.

Scheme VI

Scheme VI, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Phenylacetone is condensed with an oxalic acid ester to give 5-phenylpentanoic acid ester 601. Condensation with a substituted hydrazine provides a pyrazole ring 602. Ester reduction, alcohol alkylation, and ester hydrolysis proceed as before. Synthesis of acid 603 is completed using either steps (d)-(f) from Scheme II or steps (d)-(g) from Scheme III.

Scheme VII

Scheme VII, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. The acetylated hydroxyaryl compound 701 reacts under Williamson ether synthesis reaction conditions with an alkyl halide or similar compound to give an alkoxyaryl compound 702. Condensation with an oxalic acid ester gives 2,4-diketoester 703 as in Scheme II. The synthesis is completed using either steps (d)-(f) from Scheme II or steps (d)-g) from Scheme III.

Scheme VIII

Scheme VIII, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The bromaryl compound 801 is converted to the methoxyaryl compound 802 in the presence of a suitable metal catalyst in the presence of a base. The methyl ester is cleaved with a Lewis acid. The resulting hydroxyl compound is reacted under Williamson ether synthesis reaction conditions to give the alkoxyaryl compound 803. Alternatively, the bromaryl compound is directly reacted with the alcohol of interest to obtain the required ester 803 directly. In the depicted scheme, R ₁₀₀ -R ₁₀₆ , as will be understood by a person skilled in the art, represent any suitable group. Synthesis 804 is completed using either steps (c)-(f) from Scheme II or steps (c)-(g) from Scheme III.

Scheme IX

Scheme IX, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The bromaryl compound 901 is converted to (bromomethyl)pyrazole 904. The compound is reacted under Williamson ether synthesis reaction conditions with a suitable glycol ether to give ester 905. Transesterification with methyl ester 905 is followed by displacement of the aryl bromide using a suitable Pd ⁰ catalyst. The synthesis is completed by alkaline hydrolysis of the methyl ester to give acid 906.

Scheme X

Scheme X, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. Chlorarylcarboxylic acid ester 1001 is coupled with an organozinc reagent in the presence of copper(1) iodide to give 1002. The ester functionality is converted to methyl ketone 1003. Condensation with diethyl oxalate provides a β-diketone compound. Synthesis 1004 is completed using either steps (c)-(f) from Scheme II or steps (c)-(g) from Scheme III.

Scheme XI

Scheme XI, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The pyrazole ester 1101 is obtained via steps (a)-(c) of Scheme II. The compound under Mitsunobu reaction conditions is coupled with the appropriate alcohol to give the alkylated product 1102. Synthesis of acid 1103 is completed using either steps (d)-(f) from Scheme II or steps (d)-(g) from Scheme III.

Scheme XII, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The pyrazole ester 1201 is obtained by steps (a) to (c) of scheme II. The compound is coupled with an alkyl halide in the presence of a base to give 1202. Synthesis of acid 1203 is completed using either steps (d)-(f) from Scheme II or steps (d)-(g) from Scheme III.

Scheme XIII, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. The 2,4-diketoester is condensed with a nitroaromatic compound such as 4-nitroaniline to give the pyrazole moiety 1301. Reduction of the nitro group is followed by reductive amination to give the (dialkyl)amino compound 1302. The synthesis of acid 1303 is completed using either steps (d) - ( f) from scheme II, or steps (d) - (g) from scheme III.

Scheme XIV, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The 2,4-diketoester is condensed with hydrazine to give pyrazole 1401, which is then alkylated with a substituted benzyl bromide to give 1402. Reduction to an amine is followed by reductive alkylation to give a substituted amine 1403. Synthesis of acid 1404 is completed using either steps (d) - (f) from scheme II, or steps (d) - (g) from scheme III.

Scheme XV, depicted above, can be used to synthesize some of the illustrative compounds disclosed in this document. The (bromomethyl)pyrazole 1501 obtained by steps (a)-(e) of Scheme II is converted to the phosphonium salt 1502. Treatment with a base provides the formation of phosphoranilide 1503; Wittig reaction with an appropriate aldehyde provides alkene 1504. The alkene can optionally be hydrogenated to give alkane 1506. The synthesis is completed by hydrolysis of the ester to give alkene 1505 or alkane 1507, respectively.

Scheme XVI, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Acetonitrile is condensed with an oxalic acid ester to give the ketoester product, which can be isolated as its salt 1601. After neutralization of the salt, condensation follows with a substituted hydrazine to give the 5-aminopyrazole compound 1602. The amino functionality is then displaced by reaction with an organohalide in a palladium(0) mediated reaction to give 1603 and then introduce a protecting group in the form of its Boc-carbamate 1604. Ester reduction, alcohol alkylation and ester hydrolysis proceed as before to give acid 1605. The Boc protecting group is removed under acidic conditions to give 1606.

Scheme XVII, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. The 2-ketosuccinic acid ester is condensed with a substituted hydrazine to give the 5-hydroxypyrazole compound 1701, shown herein as its ketoautomer. The hydroxy group is alkylated with an electrophilic arene such as 2-fluoronitrobenzene to give the ester 1702. The nitro functionality is removed by stepwise reduction with zinc(0) to amine 1703 followed by deamination with alkyl nitrite to give 1704. The synthesis of acid 1705 is completed using either steps (d) - (f) from scheme II, or steps (d) - (g) from scheme III.

Scheme XVIII, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Nitroacetophenone 1801 is reacted under Claisen reaction conditions with an oxalic acid ester to give 2,4-diketoester 1802, which is then reacted with a substituted hydrazine in step (c) to construct a pyrazole core 1803, which is alkylated to give 1804. Functional group ester is reduced to an alcohol (not shown) and alkylated to give ester 1805. At this point, the nitro group is reduced with zinc to give amine 1806 and acylated using standard coupling reagents to give amide 1807. The synthesis is completed by basic hydrolysis of the ester with obtaining carboxylic acid 1808.

Scheme XIX, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. In route (a), amine 1806 prepared using the method of Scheme XVIII is treated with organonitrile in the presence of disulfide to give a thioether, which is oxidized to sulfone 1901. In route (b), amine 1806 is reacted with sulfonyl chloride to give sulfonamide 1903. In route ( c) amine 1806 is treated with aldehyde under reductive amination conditions to give amine 1905. In routes (a), (b) and (c), the synthesis is completed by basic hydrolysis of the ester to give carboxylic acid 1902, 1904 and 1906, respectively.

Scheme XX, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. Benzyl ether 206 is obtained using steps (a)-(e) of Scheme II. Treatment with acid provides cleavage of both the ester group and the methyl ester to give acid 2001. If necessary, the synthesis can be continued with a Fischer esterification reaction until 2002, alkylation of the phenol under basic conditions, and hydrolysis of the methyl ester to give acid 2003.

Scheme XXI, depicted above, can be used to obtain some of the illustrative compounds disclosed in this document. The carboxylic acid 207 is obtained using steps (a)-(f) of Scheme II. Treatment of the acid with an alkylsulfonamide provides ester 2101.

Scheme XXII, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. Aryllithium 2201, obtained by lithiation, halogen-metal exchange, or other methods that are available in the art, is reacted with N-methyl-N-methoxyacetamide, which provides an acetyl compound 2202, which can be converted to the desired product by any of the previous schemes.

Scheme XXIII, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. The carboxylic acid 2301 is converted to the corresponding alkoxyamide 2302 using standard amide formation procedures. The alkoxyamide is then reacted with a suitable organolithium reagent to provide the ketone compound 2303, which can be converted to the desired product by any of the previous schemes.

Scheme XXIV, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. The aryl halide 2401 obtained using any of the methods disclosed herein is converted to the corresponding arylamine 2402. This conversion can be carried out using a copper-based catalyst or other techniques known in the art. The synthesis can then be completed using the methods disclosed herein.

Scheme XXV, depicted above, can be used to obtain certain exemplary compounds disclosed in this document. The aryl halide 2501 obtained using any of the methods disclosed herein is converted to the corresponding arylamide 2502. This conversion can be carried out using a copper-based catalyst or other techniques known in the art. The synthesis can then be completed using the methods disclosed herein.

Scheme XXVI, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. An aryl halide 2601 prepared using any of the methods disclosed herein is converted to the corresponding aryl nitrile 2602. This conversion can be accomplished using a Pd-based catalyst or other techniques known in the art. The synthesis can then be completed using the methods disclosed herein.

Scheme XXVII, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. The carboxylic acid 2701 obtained using any of the methods disclosed herein is converted to the corresponding carboxylate salt 2702. This conversion can be performed using a metal hydroxide or metal oxide. The metal may be selected from alkali metals, alkaline earth metals, or other metals.

Scheme XXVIII, depicted above, can be used to obtain certain illustrative compounds disclosed in this document. The aryl or heteroaryl halide 2801 is converted to the corresponding hydrazine 2802. Synthesis of the pyrazole core is carried out by condensation with the appropriate carbonyl compound as disclosed herein. The amino functionality on the aryl or heteroaryl moiety 2801 may be protected by attaching a suitable protecting group, such as a SEM protecting group. The protecting group can be removed at a convenient point in the synthesis using methods known in the art.

Intermediates

The following intermediates have been synthesized for use in the preparation of the compounds of the present invention.

Intermediate A-1: 1-(1-methyl-1H-indol-6-yl)ethan-1-one

6-Bromo-1-methyl-1H-indole. A mixture of 6-bromo-1H-indole (5 g, 25.50 mmol, 1.00 equiv.), K ₂ CO ₃ (7 g, 50.65 mmol, 2.00 equiv.) and CH ₃ I (7, 3 g, 51.43 mmol, 2.00 equiv.) in acetone (100 ml) was stirred for 16 hours at 55°C, then cooled to rt, diluted with 100 ml H ₂ O and extracted with with 2×200 ml EtOAc. The combined organic layers were washed with 100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 3.4 g (63%) of the title in the compound header as a yellow oil. LC-MS: (ES, mass/charge): 208. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (dt, J=1.6, 0.7 Hz, 1H), 7.49 (dd, J=8.4, 0.6Hz, 1H), 7.34 (d, J=3.1Hz, 1H), 7.13 (dd, J=8.4, 1.8Hz, 1H), 6.43 (dd, J=3.1, 0.9 Hz, 1H), 3.77 (s, 3H).

1-(1-Methyl-1H-indol-6-yl)ethan-1-one. To a solution of 6-bromo-1-methyl-1H-indole (3.4 g, 16.19 mmol, 1.00 equiv) in THF (100 ml) was added BuLi (12 ml, 2.00 equiv, M) dropwise with stirring at -78°C. The solution was stirred for 1 hour, then N-methoxy-N-methylacetamide (4.1 g, 39.76 mmol, 2.50 equiv.) was added dropwise with stirring at -78°C. The solution was stirred for 30 minutes, then warmed to rt and stirred an additional 2 hours. The reaction mixture was cooled to 0°C, then the reaction was stopped by adding 1 M HCl and was extracted with 2×200 ml EtOAc. The combined organic layers were washed with 100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 1.9 g (68%) of the title in the title compound as a yellow solid. LC-MS: (ES, mass/charge): 173. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 8.12 (dt, J=1.5, 0.8 Hz, 1H), 7, 70-7.59 (m, 2H), 7.57 (d, J=3.0 Hz, 1H), 6.51 (dd, J=3.0, 0.9 Hz, 1H), 3.88 (s, 3H), 2.63 (s, 3H).

Intermediate A-2: 1-(1-methyl-1H-indazol-6-yl)ethan-1-one

1-(1-Methyl-1H-indazol-6-yl)ethan-1-one. _n- BuLi (10 ml, 2.00 equiv.) with stirring. The solution was stirred for 60 minutes. at this temperature, then N-methoxy-N-methylacetamide (3 g, 29.09 mmol, 2.50 equiv.) was added and the solution was stirred for an additional 60 minutes. at this temperature. The resulting solution was stirred for 1 h at RT, cooled to 0°C, the reaction was stopped by adding HCl (1 M) and was extracted with 2×100 ml EtOAc. The combined organic layers were washed with 50 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 1.5 g (73%) of the title in the compound header as a yellow oil. LC-MS: (ES, mass/charge): 174. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.36 (q, J=1.1 Hz, 1H), 8.16 (d, J=1.0Hz, 1H), 7.86 (dd, J=8.5, 0.8Hz, 1H), 7.69 (dd, J=8.5, 1.4Hz, 1H), 4.16 (s, 3H), 2.70 (s, 3H).

The following acetylarenes were prepared by similar methods.

The following acetylarene intermediates were prepared by Scheme XXII.

Intermediate A-9: 1-(3-cyclobutoxyphenyl)ethan-1-one

To a mixture of 1-(3-hydroxyphenyl)ethan-1-one (4.5 g, 33.05 mmol, 1.00 equiv.) and Cs ₂ CO ₃ (10.78 g, 33.09 mmol, 1.00 equiv.) ) in DMA (50 ml) was added dropwise bromocyclobutane (9.0 g, 66.67 mmol, 2.00 equiv.) with stirring at rt. The resulting mixture was stirred for 16 hours at 130°C, then cooled and diluted with 200 ml EtOAc. The combined organic layers were washed with 2×200 ml H ₂ O and 2×200 ml brine, then dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 5.0 g (80%) of the title compound as a colorless oil. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 7.53 (ddd, J=7.6, 1.7, 1.1 Hz, 1H), 7.41 (t, J=7.9 Hz , 1H), 7.32 (dd, J=2.6, 1.6 Hz, 1H), 7.10 (ddd, J=8.1, 2.7, 1.0 Hz, 1H), 4, 83-4.67 (m, 1H), 2.55 (s, 3H), 2.47-2.31 (m, 2H), 2.14-1.94 (m, 2H), 1.88- 1.72(m, 1H), 1.72-1.56(m, 1H).

Intermediate A-10: 1-[3-(oxetan-3-ylmethoxy)phenyl]ethan-1-one

In a flask under N ₂ was combined a solution of oxetan-3-ylmethanol (3.24 g, 36.77 mmol, 1.00 equiv.) in THF (100 mL), 1-(3-hydroxyphenyl)ethan-1-one ( 5 g, 36.72 mmol, 1.00 equiv.) and PPh ₃ (14.5 g, 1.50 equiv.) followed by DEAD (8.3 g, 47.66 mmol, 1.30 equiv.) .) with stirring at 0°C. The resulting solution was stirred for 12 hours at rt, then extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (0-20%) to give 4.4 g (58%) of the title compound as light yellow oils. LC-MS: (ES, mass/charge): 206.90. H-NMR: δ _H (300 MHz, DMSO-d ₆ ) 7.56 (1H, ddd, J=7.6, 1.6, 1.0 Hz), 7.45 (2H, m), 7, 23 (1H, ddd, J=8.2, 2.7, 1.1 Hz), 4.71 (2H, dd, J=7.9, 6.0 Hz), 4.44 (2H, t, J=6.0, 6.0 Hz), 4.26(2H, d, J=6.7 Hz), 3.39(1H, m), 2.57(3H, s).

The following alkylated compounds were obtained from the Williamson synthesis of 3-hydroxyacetophenone.

Intermediate A-19: 1-(3,5-dimethoxyphenyl)ethan-1-one

In a flask were combined 1-(3,5-dihydroxyphenyl)ethan-1-one (2 g, 13.15 mmol, 1.00 equiv.), iodomethane (6.5 g, 45.79 mmol, 4.00 equiv.). ), K ₂ CO ₃ (3.6 g, 25.86 mmol, 2.00 equiv.) and acetone (40 ml). The resulting mixture was stirred for 16 hours at 56° C., then cooled to rt, diluted with 100 ml of water and extracted with 2×50 ml of EtOAc. The combined organic layers were washed with 20 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 2 g (84%) of the title product as a colorless oil. LC-MS: (ES, mass/charge): 181. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 7.07 (d, J=2.3 Hz, 2H), 6.77 (t, J=2.3 Hz, 1H), 3.89-3.71 (m, 6H), 2.56 (s, 3H).

Intermediate A-20: 1-(3,5-diethoxyphenyl)ethan-1-one

In a flask were combined 1-(3,5-dihydroxyphenyl)ethan-1-one (5 g, 32.86 mmol, 1.00 equiv.), iodoethane (20 g, 128.23 mmol, 4.00 equiv.), K ₂ CO ₃ (18 g, 130.43 mmol, 4.00 equiv.) and acetone (100 ml). The resulting mixture was heated to reflux temperature overnight, then cooled to rt and extracted with 3×100 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 6 g (88%) of the title compound as a brown solid. LC-MS: (ES, mass/charge): 208.95.

Intermediate A-21: 1-(3-ethoxy-5-methoxyphenyl)ethan-1-one

1-(3-Hydroxy-5-methoxyphenyl)ethan-1-one. To a mixture of 1-(3,5-dihydroxyphenyl)ethan-1-one (5.0 g, 32.86 mmol, 1.00 equiv.), K ₂ CO ₃ (6.85 g, 49.56 mmol, 1 50 equiv.) and acetone (100 mL) were added dropwise MeI (4.67 g, 32.89 mmol, 1.00 equiv.) with stirring at rt. The resulting solution was heated to reflux temperature for 2 hours, concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:3) to give 2 g (37%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 167.

1-(3-Ethoxy-5-methoxyphenyl)ethan-1-one. To a mixture of 1-(3-hydroxy-5-methoxyphenyl)ethan-1-one (2 g, 12.04 mmol, 1.00 equiv.), K ₂ CO ₃ (2.5 g, 18.09 mmol, 1 50 equiv.) and DMF (50 ml) were added dropwise with EtI (2.8 g, 17.95 mmol, 1.00 equiv.) with stirring at RT. The resulting solution was stirred for 16 hours at 90° C, diluted with 100 ml EtOAc, washed with 1×100 ml water and 1×100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1 :5) to give 950 mg (41%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 195. ¹ H-NMR: (DMSO, ppm): δ: 7.06 (dq, J=2.9, 1.4 Hz, 2H), 6.75 (t, J=2.3 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.34 (t, J=6.9 Hz , 3H).

Intermediate A-22: 1-[2-(propan-2-yloxy)-1,3-oxazol-5-yl]ethan-1-one

2-Hydroxy-1,3-oxazole-5-carboxylic acid. A solution of ethyl 2-chloro-1,3-oxazole-5-carboxylate (3 g, 17.09 mmol, 1.00 equiv) and LiOH (1.7 g, 70.98 mmol, 4.00 equiv) in THF/H ₂ O (60/15 ml) was stirred for 16 hours at 30°C. Then the pH was adjusted to 4 with 1 M HCl and the resulting solution was extracted with 4×50 ml EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 2 g (91%) of the title compound as a yellow solid. LC-MS: (ES, mass/charge): 129.

2-Hydroxy-N-methoxy-N-methyl-1,3-oxazole-5-carboxamide. N-methoxy-N-methylamine hydrochloride solution (1.8 g, 18.45 mmol, 1.20 equiv.), HATU (7.6 g, 20.54 mmol, 1.30 equiv.), DIEA (6 g , 46.43 mmol, 3.00 equiv.) and 2-hydroxy-1,3-oxazole-5-carboxylic acid (2 g, 15.50 mmol, 1.00 equiv.) in DMF (60 ml) were stirred in for 5 hours at room temperature. The resulting mixture was concentrated in vacuo and purified by silica gel chromatography using CH ₂ Cl ₂ /MeOH (50:1) to give 1.3 g (49%) of the title compound as a yellow solid. LC-MS: (ES, mass/charge): 173.

N-methoxy-N-methyl-2-(propan-2-yloxy)-1,3-oxazole-5-carboxamide. A mixture of 2-hydroxy-N-methoxy-N-methyl-1,3-oxazole-5-carboxamide (1.8 g, 10.46 mmol, 1.00 equiv.), 2-iodopropane (3.6 g, 2 00 equiv.), K ₂ CO ₃ (2.9 g, 2.00 equiv.) and DMF (15 ml) in a 20 ml sealed tube were stirred for 16 hours at 90°C. The reaction mixture was cooled to rt, diluted with 20 ml H ₂ O and extracted with 4×20 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using CH ₂ Cl ₂ /MeOH (100:1) to give 1.5 g (67%) of the title compound as yellow solid. LC-MS: (ES, mass/charge): 214.

1-[2-(Propan-2-yloxy)-1,3-oxazol-5-yl]ethan-1-one. To a solution of N-methoxy-N-methyl-2-(propan-2-yloxy)-1,3-oxazole-5-carboxamide (1.5 g, 7.00 mmol, 1.00 equiv.) in THF (40 ml) under N ₂ at -78° C. was added in portions of MeMgBr (21 ml, 3.00 equiv.). The resulting solution was stirred for 2 hours at rt, cooled to 0°C, the reaction was stopped by adding HCl (1 M) and was extracted with 2x50 ml EtOAc. The combined organic layers were washed with 30 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 670 mg (57%) of the title compound as a yellow solid. LC-MS: (ES, mass/charge): 169.

Intermediate A-23: 1-[1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]ethan-1-one

N-methoxy-N,1,3-trimethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide. Solution of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2 g, 10.19 mmol, 1.00 equiv.) methoxy(methyl)amine hydrochloride (1.06 g, 10.87 mmol, 1.10 equiv.), DIEA (4 g, 30.95 mmol, 3.00 equiv.) and HATU (5.8 g, 15.26 mmol, 1.50 equiv.) in DMF ( 30 ml) was stirred for 2 hours at RT, diluted with 100 ml of water and extracted with 2×100 ml of EtOAc. The combined organic layers were washed with 100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:3) to give 2.2 g (90%) of the indicated in the title compound as a yellow solid. LC-MS: (ES, mass/charge): 240.

1-[1,3-Dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]ethan-1-one. _{Methylmagnesium} bromide (1.0 M in THF , 29 ml, 3.00 equiv.) with stirring. The resulting solution was stirred for 2 hours at room temperature, then cooled to 0°C and then the reaction was stopped by adding aq. HCl. The resulting solution was diluted with 100 ml H ₂ O and extracted with 2×200 ml EtOAc. The combined organic layers were washed with 50 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel column chromatography using EtOAc/petroleum ether (1:3) to give 1.4 g (78% ) of the title compound as a white solid.

LC-MS: (ES, mass/charge): 195. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 3.86 (s, 3H), 2.52 (s , 4H), 2.39 (s, 3H).

Intermediate A-24: 1-(5-methoxythien-2-yl)ethan-1-one

Mixture of 1-(5-chlorothien-2-yl)-1-ethanone (11 g, 96.35 mmol, 1.00 equiv.), Cs ₂ CO ₃ (22 g, 1.20 equiv.) and Brettphos Pd G3 (550 mg) in MeOH (60 ml) was heated in a sealed test tube for 1 hour at 100°C using microwave radiation. The resulting mixture was concentrated in vacuo, then extracted with 3×100 ml EtOAc. The combined organic layers were dried over anhydrous MgSO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1/50) to give 5 g (33%) of the title product as a yellow solid.

Intermediate A-25: 1-[2-(2-methylpropoxy)-1,3-thiazol-5-yl]ethan-1-one

To a solution of 1-(2-bromo-1,3-thiazol-5-yl)ethan-1-one (2 g, 9.71 mmol, 1.00 equiv.) in 2-methylpropan-1-ol (15 ml ) in a sealed 40 ml tube under N ₂ were added successively Cs ₂ CO ₃ (6.4 g, 19.64 mmol, 2.00 equiv.) and Brettphos Pd G3 (440 mg, 0.49 mmol, 0.05 equiv.). The resulting solution was stirred for 1 hour at 90°C. The solution was cooled, diluted with 50 ml H ₂ O and extracted with 2×100 ml EtOAc. The combined organic layers were washed with 50 ml aq. NaCl solution, dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel column using EtOAc/petroleum ether (1:10) to give 550 mg (28%) of the title compound as a yellow oil.

Intermediate A-26: 1-[5-(2-methylpropoxy)thien-2-yl]ethan-1-one

1-(5-Hydroxythien-2-yl)ethan-1-one. BBr ₃ (180 ml) was added dropwise to a solution of 1-(5-methoxy-thien-2-yl)ethan-1-one with stirring at RT. The resulting solution was stirred for 2 days at 35°C. The reaction mixture was cooled with a water/ice bath. Then, in the reaction mixture, the reaction was stopped by adding 500 ml of water/ice. The resulting solution was diluted with 500 ml CH ₂ Cl ₂ . The pH of the solution was adjusted to 7-8 with (sat.) NaHCO ₃ (aq.) (500 mol/l). The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:10). This gave the title compound as a red oil (5.0 g, 61%).

1-[5-(2-Methylpropoxy)thien-2-yl]ethan-1-one. To a solution of the product from the previous step (800 mg, 5.63 mmol, 1.00 equiv.) in DMF (20 ml) was added Cs ₂ CO ₃ (3.67 g, 11.26 mmol, 2.00 equiv.) with followed by dropwise addition of 1-iodo-2-methylpropane (2.07 g, 11.25 mmol, 2.00 equiv.) with stirring at rt. The resulting solution was stirred for 16 hours at 90°C. The resulting solution was diluted with 100 ml EtOAc, then washed with 2×100 ml water and 2×100 ml brine. The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:10). This gave the title compound as a yellow oil (600 mg, 54%).

Intermediate A-27: 1-(4-methoxythien-2-yl)ethan-1-one

NaOMe (5.4 ml, 2 .00 equiv., 5.4 M) at room temperature and then CuBr (627 mg, 4.38 mmol, 0.30 equiv.) was added at room temperature. The resulting solution was stirred for 16 hours at 100° C., then diluted with 100 ml EtOAc, washed with 2×100 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc/petroleum ether (1:20) to give 700 mg (31%) of the title product as a yellow oil.

Intermediate A-28: 1-[2-(2-methylpropyl)-1,3-oxazol-5-yl]ethan-1-one

Ethyl 2-(2-methylpropyl)-1,3-oxazole-5-carboxylate. Copper(I) iodide ( ₁ .5 g, 7.88 mmol, 0.50 equiv.). This was followed by the addition of bromo(2-methylpropyl)zinc (15 ml, 2.00 equiv.) at -5°C. The resulting solution was stirred for 3 hours at room temperature. Then, in the reaction mixture, the reaction was stopped by adding aq. 1 M HCl. The resulting solution was extracted with 2×100 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:5). This gave the title compound as a red oil (1.3 g, 39%).

2-(2-Methylpropyl)-1,3-oxazole-5-carboxylic acid. To a solution of the product from the previous step (1.3 g, 6.59 mmol, 1.00 equiv.) in THF/H ₂ O (20/5 ml) was added LiOH (600 mg, 25.05 mmol, 4.00 equiv. .). The resulting solution was stirred for 3 hours at room temperature. The reaction mixture was cooled with a water/ice bath. The pH of the solution was adjusted to 1 with aq. 1 M HCl. The resulting solution was extracted with 2×50 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This gave the title compound as a red solid (1 g, 90%).

1-[2-(2-Methylpropyl)-1,3-oxazol-5-yl]ethan-1-one. To a solution of the product from the previous step (1 g, 5.91 mmol, 1.00 equiv.) in Et ₂ O (30 ml) under N ₂ was added MeLi (7.4 ml, 2.00 equiv.). The resulting solution was stirred for 3 hours at 0° C. in a water/ice bath. Then, in the reaction mixture, the reaction was stopped by adding aq. HCl (1 M). The resulting solution was extracted with 2×50 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:5). This gave the title compound as a red oil (800 mg, 81%).

Intermediate A-29: 1-(1-methyl-1H-1,3-benzodiazol-6-yl)ethan-1-one

N-methoxy-N,1-dimethyl-1H-1,3-benzodiazol-6-carboxamide. _Methoxy ( _methyl )amine hydrochloride (2.78 g, 28.50 mmol, 1.00 equiv), EDC (6.54 g, 42.13 mmol, 1.20 equiv) followed by DMAP (3.46 g, 28.32 mmol, 1.00 equiv.) parts at rt. The resulting solution was stirred for 16 hours, concentrated in vacuo and purified by silica gel chromatography using CH ₂ Cl ₂ /MeOH (100:1) to give 4, 0 g (64%) of the title compound as a yellow solid. LC-MS: (ES, mass/charge): [M+1] = 220.

1-(1-Methyl-1H-1,3-benzodiazol-6-yl)ethan-1-one. To a solution of the product from the previous step ( _2.0 g, 9.12 mmol, 1.00 equiv.) in THF (60 mL) under N stirring at -60°C. The resulting mixture was stirred at this temperature for 30 minutes, warmed to rt, then stirred for 2 h at rt. The reaction mixture was then quenched by adding water/ice. The resulting solution was extracted with 100 ml EtOAc, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using CH ₂ Cl ₂ /MeOH (50:1) to give 1.3 g (82%) of the indicated in the title compound as a yellow solid.

Intermediate A-30: 3-acetyl-N-(propan-2-yl)benzamide

To a suspension of 3-acetylbenzoic acid (10 g, 60.92 mmol), HATU (20 g, 52.60 mmol) and propane-2-amine (4 g, 67.67 mmol) in DMF (180 ml) at - 5°C was added dropwise DIEA. The resulting mixture was stirred at room temperature for 2 hours under N ₂ then poured into 100 ml H ₂ O and extracted with EtOAc (3×100 ml). The combined organic layers were washed with 300 ml brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. This resulted in 11 g (88%) of the title product as a yellow solid.

The following 2,4-dioxobutanoate esters have been synthesized for use in preparing the compounds of the present invention, including but not limited to use in Scheme I.

Intermediate B-1: methyl 4-(2-methoxyphenyl)-2,4-dioxobutanoate

Dimethyl oxalate (2.36 g, 19.99 mmol, 3 .00 equiv.), then MeONa (3.7 ml, 3.00 equiv., 5.4 M) was added. The resulting solution was stirred overnight at 30°C, then the reaction was stopped by adding water/ice. The pH of the solution was adjusted to 5 with aq. 1 M HCl. The resulting solution was extracted with 3×50 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/hexane (1/4). This gave the title compound as a yellow solid (1.2 g, 76%).

Intermediate B-2: methyl 4-(3-methoxyphenyl)-2,4-dioxobutanoate

NaOMe (30 ml) and dimethyl oxalate (10.2 g, 86.38 mmol, 1.3 equiv.). The resulting solution was stirred for 8 hours at room temperature. The reaction mixture was cooled to 0° C. with a water/ice bath. The resulting solution was diluted with 200 ml EtOAc. The pH of the solution was adjusted to 3 with aq. HCl (3 mol/l). The resulting solution was extracted with 2×300 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This gave the title compound as a yellow solid (11 g, 70%).

Intermediate B-3: methyl 4-[3-(oxetan-3-ylmethoxy)phenyl]-2,4-dioxobutanoate

In a 100 ml flask was combined a solution of 1-[3-(oxetan-3-ylmethoxy)phenyl]ethan-1-one (prom. Comp. A-10, 3 g, 14.55 mmol, 1.00 equiv.) in MeOH (40 ml), dimethyl oxalate (3.42 g, 28.96 mmol, 2.00 equiv.) and a solution of MeONa (2.36 g, 43.70 mmol, 3.00 equiv.) in MeOH (8 ml) . The resulting solution was stirred for 12 hours at rt, then poured into ice/water. The pH was adjusted to 3 with HCl. The solids that formed were collected by filtration to give 3.2 g (75%) of the title compound as a light yellow solid. LC-MS:(ES, mass/charge): 293.0. ¹ H-NMR: δ _H (300 MHz, DMSO-d ₆ ) 7.68 (1H, d, J=7.7 Hz), 7.53 (2H, m), 7.30 (1H, m), 7.14 (1H, s), 4.72 (2H, dd, J=7.9, 6.0 Hz), 4.45 (2H, t, J 6.0, 6.0 Hz), 4. 30 (2H, d, J=6.7 Hz), 3.86 (3H, s), 3.40 (1H, tt, J=8.0, 8.0, 6.3, 6.3 Hz) .

The following substituted 4-aryl-2,4-dioxobutanoate esters were prepared by the Claisen condensation reaction of 1-arylethanone with an oxalic acid ester.

Intermediate B-39: ethyl 4-[2-(2-methylpropoxy)-1,3-thiazol-5-yl]-2,4-dioxobutanoate

To a solution of prom. conn. A-25 (500 mg, 2.51 mmol, 1.00 equiv.) in THF (10 ml) was added successively diethyl oxalate (1100 mg, 7.53 mmol, 2.00 equiv.) and t-BuOK (850 mg, 7.58 mmol, 3.00 equiv.). The resulting solution was stirred for 4 hours at room temperature followed by dilution with 20 ml H ₂ O, extraction with 2×30 ml EtOAc, and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:4). This gave the title compound as a yellow solid (400 mg, 53%).

Intermediate B-40: ethyl 2,4-dioxo-5-phenylpentanoate

To a solution of 1-phenyl-2-propanone (1 g, 8.32 mmol, 1.00 equiv.) in THF (25 ml) was added portions of NaH (269 mg, 11.21 mmol, 1.50 equiv.) at 0 °C for 30 min. followed by the addition of diethyl oxalate (1.64 g, 11.22 mmol, 1.50 equiv.). The resulting solution was stirred for 1 hour at room temperature, then cooled to 0°C. Then, in the reaction mixture, the reaction was stopped by adding 20 ml of water. The resulting solution was extracted with 3×50 ml EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:40) to give 700 mg (36% ) of the title product as a yellow liquid.

The following substituted ketoesters have also been used in the synthesis of pyrazoles.

Intermediate B-41: methyl 2,4-dioxo-4-(1-propyl-1H-indazol-6-yl)butanoate

Intermediate B-42: methyl 4-(3-cyclobutoxyphenyl)-2,4-dioxobutanoate

The following arylhydrazine intermediates have been synthesized for use in the preparation of the compounds of the present invention, including but not limited to use in Scheme I.

Intermediate C-1: 2-(difluoromethoxy)phenyl]hydrazine trifluoroacetate

Boc-protected 2-(difluoromethoxy)phenyl]hydrazine. To a solution of 1-bromo-2-(difluoromethoxy)benzene (8.0 g, 35.87 mmol, 1.00 equiv), (tert-butoxy) carbohydrazide (5.68 g, 42.98 mmol, 1.20 equiv.) and BrettPhos Pd G3 (1.74 g, 1.92 mmol, 0.05 equiv.) in dioxane (60 ml) under N ₂ were added in portions of Cs ₂ CO ₃ (11.70 g, 35.91 mmol , 1.00 equiv.) at room temperature. The resulting solution was stirred for 16 hours at 100°C, then diluted with 200 ml EtOAc, washed with 200 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 8.0 g (81%) of the title compound as an orange solid. LC-MS: (ES, mass/charge): 275. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 7.29-7.22 (m, 1H), 7 .07 (q, J=7.7 Hz, 2H), 6.80-6.68 (m, 2H), 1.42 (s, 9H).

2-(Difluoromethoxy)phenyl]hydrazine trifluoroacetate. A solution of the product from the previous step (2.0 g, 7.29 mmol, 1.00 equiv.) and TFA (10 ml) in CH ₂ Cl ₂ (20 ml) was stirred for 2 hours at room temperature, then concentrated under vacuo to give 1.0 g (48%) of the title compound as a brown oil. LC-MS: (ES, mass/charge): 175.

The following arylhydrazines were synthesized from the corresponding aryl halides using similar procedures.

First, the free amino groups of the following reactants were protected with SEM groups (NaH; SEM-Cl). Treatment of the coupled product with TFA to remove the Boc groups also removed the SEM protecting groups.

Intermediate C-12: 7-hydrazinyl-1-methyl-1H-1,2,3-benzotriazole trifluoroacetate

2-Bromo-N-methyl-6-nitroaniline. A mixture of 1-bromo-2-fluoro-3-nitrobenzene (7 g, 31.82 mmol, 1.00 equiv.), K ₂ CO ₃ (8.8 g, 63.21 mmol, 2.00 equiv.) and CH ₃ NH ₂ (10 ml, 33%) in CH ₂ Cl ₂ (50 ml) was stirred for 16 hours at rt, then diluted with 100 ml of water. The resulting solution was extracted with 2×200 ml CH ₂ Cl ₂ . The combined organic layers were washed with 50 ml brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 7 g (95%) of the title compound as a red oil. LC-MS: (ES, mass/charge): 230. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (ddd, J=9.8, 8.0, 1.6 Hz, 2H) , 6.70 (t, J=8.0 Hz, 1H), 6.43-6.19 (m, 1H), 2.71 (d, J=5.3 Hz, 3H).

6-Bromo-1-N-methylbenzene-1,2-diamine. A mixture of the product from the previous step (8 g, 34.62 mmol, 1.00 equiv.) and Zn (4 g, 62.50 mmol, 2.00 equiv.) in AcOH (120 mL) was stirred for 16 hours at k.t. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in 300 ml CH ₂ Cl ₂ , washed with 100 ml NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated in vacuo to give 4 g (57%) of the title compound as a black oil. LC-MS: (ES, mass/charge): 201.

7-Bromo-1-methyl-1H-1,2,3-benzotriazole. To a solution of the product from the previous step (4 g, 19.89 mmol, 1.00 equiv.) in HBr/H ₂ O (60 ml) at 5°C was added dropwise a solution of NaNO ₂ (2.07 g, 1.50 equiv.) in H ₂ O (10 ml) with stirring. The solution was stirred for 4 hours at 15-20°C. The pH was adjusted to 8 with NaHCO ₃ (3 mol/l). The resulting solution was extracted with 2×200 ml EtOAc. The combined organic layers were washed with 100 ml brine, dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 4 g (95%) of the indicated the title compound as a black solid. LC-MS: (ES, mass/charge): 212. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (dd, J=8.3, 0.8 Hz, 1H), 7.84 -7.73 (m, 1H), 7.31 (dd, J=8.4, 7.5 Hz, 1H), 4.51 (s, 3H).

7-Hydrazinyl-1-methyl-1H-1,2,3-benzotriazole trifluoroacetate was prepared from the previous compound using procedure C-1. LC-MS: (ES, mass/charge): 163.

Intermediate C-13: [(2-chlorophenyl)methyl]hydrazine dihydrochloride

To a solution of hydrazine hydrate (85%) (31 g, 8.50 equiv.) in EtOH (100 ml) was added dropwise a solution of 1-chloro-2-(chloromethyl)benzene (10 g, 62.10 mmol, 1.00 equiv.) in EtOH (50 ml) for 1 hour at 70°C. The resulting solution was stirred for 1 hour at 70° C., concentrated in vacuo, diluted with water and extracted with EtOAc three times. The combined organic layers were cooled to 0°C, then added 4N. HCl solution in dioxane. The solids that formed were collected by filtration to give 6.1 g (63%) of the title product as a white solid.

Intermediate D-1: Ethyl 5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate

Ethyl 3-cyano-2-(potassiumoxy)prop-2-enoate. To a solution of diethyl oxalate (5.06 g, 34.62 mmol, 1.00 equiv.) in CH ₃ CN (20 ml) was added t-BuOK (3.90 g, 34.76 mmol, 1.12 equiv.) in parts at rt. The resulting solution was stirred for 1.5 hours at rt. The solids that formed were collected by filtration. This gave 5.09 g (82%) of the title product as a yellow solid.

Ethyl 5-amino-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate. To a solution of the product from the previous step (2.0 g, 11.16 mmol, 1.00 equiv.) in 1,4-dioxane (20 mL) was added dropwise TFA (2 mL) with stirring at rt. stirred at room temperature for 30 min. Prom was added to it in parts. conn. C-13 (2.0 g, 12.77 mmol, 1.15 equiv.) at rt The resulting solution was stirred overnight at rt, then diluted with 200 ml EtOAc, washed with 2× 200 ml brine, dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:3) to give 1.8 g (58%) of the title compound as yellow oils.

Ethyl 1-[(2-chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazole-3-carboxylate.

Provide a solution of the product from the previous step (1.0 g, 3.57 mmol, 1.00 equiv), iodobenzene (768 mg, 3.76 mmol, 1.05 equiv), Brettphos Pd G3 precatalyst (326 mg, 0 .36 mmol, 0.10 equiv.) and Cs ₂ CO ₃ (1.4 g, 4.30 mmol, 1.20 equiv.) in 1,4-dioxane (20 ml). The resulting solution was stirred in a sealed tube under N ₂ atmosphere at 90° C. for 3 hours. The resulting solution was diluted with 200 ml EtOAc, washed with 2×200 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using petroleum ether: EtOAc:DCM (3:1:0.1) to give 1.3 g (102%) of the title product as a yellow solid.

Ethyl 5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate. Di-tert- butyl dicarbonate (980 mg, 4.49 mmol, 2.00 equiv.) at rt. The resulting solution was refluxed overnight. The resulting solution was diluted with 200 ml EtOAc, washed with 2x100 ml brine, dried over anhydrous Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:3) to give 1.0 g (101%) of the title product as a colorless oil.

Intermediate D-2: methyl 5-(3-cyclopropoxyphenyl)-1H-pyrazole-3-carboxylate

Solution prom. conn. B-22 (2 g, 7.63 mmol, 1.00 equiv.) and hydrazine hydrate (540 mg, 10.00 mmol, 1.30 equiv.) in AcOH (20 ml) were stirred for 2 hours at 100 °C, then cooled. The pH was adjusted to 7 with sat. NaHCO ₃ and the resulting solution was extracted with 3×100 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/hexane (1/1) to give 1.5 g (76%) of the title compound as a light yellow solid substances. LC-MS: (ES, mass/charge): 259. ¹ H NMR (300 MHz, MeOD) δ 7.35 (m, 3H), 7.13 (d, J=21.3 Hz, 2H), 3 .92 (s, 3H), 3.84 (dp, J=6.4, 3.0, 3.0, 2.9, 2.9 Hz, 1H), 0.82 (m, 2H), 0 .72 (m, 2H).

The following substituted esters of 3-pyrazolecarboxylic acid were obtained by the condensation of methyl 4-(aryl)-2,4-dioxobutanoate with hydrazine.

Intermediate D-27: methyl 1-[(2-chlorophenyl)methyl]-5-(3-(propan-2-yl)phenyl)-1H-pyrazole-3-carboxylate

Solution prom. conn. B-13 (1.0 g, 4.03 mmol, 1.00 equiv.) and prom. conn. C-13 (1.38 g, 6.01 mmol, 1.50 equiv.) in AcOH (20 ml) was stirred for 2 hours at 100°C, then concentrated in vacuo, diluted with 200 ml EtOAc, washed with 2×100 ml sat. NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 1.05 g (71%) of the title product as a yellow solid.

Intermediate D-28: methyl 1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of prom. conn. Prom. B-2 (3.8 g, 16.09 mmol, 1.00 equiv.) in MeOH (80 ml) was added. conn. C-13 (4.8 g, 20.91 mmol, 1.30 equiv). The resulting solution was stirred for 3 hours at 65° C., then concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:2) to give the title compound as a white solid (5.5 g, 96%).

The following substituted esters of 3-pyrazolecarboxylic acid were obtained from the condensation of methyl 4-(aryl)-2,4-dioxobutanoate with various substituted hydrazines.

The following substituted 3-pyrazolecarboxylic acid esters have been prepared by the condensation of various methyl 4-aryl-2,4-dioxobutanoates with (2-chlorophenyl)hydrazine.

The following substituted 3-pyrazolecarboxylic acid esters were obtained from the condensation of Prom. conn. B-22 with various substituted hydrazines.

Intermediate E-1: 1-(bromomethyl)-2-ethoxybenzene

To a solution of (2-ethoxyphenyl)methanol (15.2 g, 99.87 mmol, 1.00 equiv.) and CBr ₄ (50.1 g, 150.00 mmol, 1.50 equiv.) in CH ₂ Cl ( 200 ml) was added in portions of PPh ₃ (39.45 g, 150.41 mmol, 1.50 equiv.) at 0°C. The resulting solution was stirred for 16 h at rt, concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 14 g (65%) of the title compound as a colorless oils. ¹ H-NMR: (CDCl ₃ , ppm): δ: 7.51-7.25 (m, 1H), 7.06-6.86 (m, 1H), 4.65 (s, 1H), 4 .16 (q, J=7.0 Hz, 1H), 1.53 (t, J=7.0 Hz, 1H).

Intermediate E-2: 1-(bromomethyl)-2-cyclopropoxybenzene

Methyl 2-cyclopropoxybenzoate. To a mixture of methyl 2-hydroxybenzoate (5.0 g, 32.86 mmol, 1.00 equiv.), Cs ₂ CO ₃ (32 g, 98.21 mmol, 3.00 equiv.) in DMA (100 ml) was added bromocyclopropane (39.8 g, 328.99 mmol, 10.00 equiv.) dropwise with stirring at rt. The resulting solution was stirred for 16 hours at 130°C, cooled, diluted with 200 ml EtOAc, washed with 2×200 ml water and 2×200 ml brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc/petroleum ether (1:6) to give 1.6 g (25%) of the title compound as a yellow oil. LC-MS: (ES, mass/charge): 193. 1H NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J=7.8, 1.8 Hz, 1H), 7.49 (ddd, J=8.9, 7.3, 1.8 Hz, 1H), 7.38 (dd, J=8.4, 1.1 Hz, 1H), 7.01 (td, J=7.5, 7.5, 1.2 Hz, 1H), 3.89 (s, 3H), 3.83 (tt, J=5.9, 5.9, 3.2, 3.2 Hz, 1H), 0 .86 (m, 4H).

(2-Cyclopropoxyphenyl)methanol. To a solution of methyl 2-cyclopropoxybenzoate (1.5 g, 7.80 mmol, 1.00 equiv.) in THF (100 mL) was added in portions of LiAlH ₄ (594 mg, 15.65 mmol, 2.00 equiv.) at 0°C. The resulting mixture was stirred for 2 hours at 0° C. in an ice/salt bath, then the reaction was stopped by adding Na ₂ SO ₄ /10 H ₂ O. Solids were removed by filtration. The resulting solution was concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 750 mg (59%) of the title compound as a yellow oil. LC-MS: (ES, mass/charge): 187. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.30 (m, 3H), 6.98 (tdd, J=7.5, 7.5 , 3.7, 1.5 Hz, 1H), 4.65 (s, 2H), 3.80 (m, 1H), 0.82 (m, 4H).

1-(Bromomethyl)-2-cyclopropoxybenzene. To a solution of (2-cyclopropoxyphenyl)methanol (750 mg, 4.57 mmol, 1.00 equiv.) and CBr ₄ (3.06 g, 9.16 mmol, 2.00 equiv.) in CH ₂ Cl (30 ml ) was added in portions of PPh ₃ (2.40 g, 9.15 mmol, 2.00 equiv.) at 0°C. The resulting solution was stirred for 2 hours at room temperature, concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:5) to give 1.0 g (96%) of the title compound as a colorless oils. ¹ H NMR (300 MHz, CDCl3) δ 7.30 (m, 3H), 6.96 (dt, J=7.6, 1.8, 1.8 Hz, 1H), 4.52 (s, 2H ), 3.84 (m, 1H), 0.83 (m, 4H).

Intermediate E-3: 2-(bromomethyl)-1-ethoxy-3-fluorobenzene

Methyl 2-ethoxy-6-fluorobenzoate. Methyl 2-fluoro-6-hydroxybenzoate mixture (500 mg, 2.94 mmol, 1.00 equiv.), K ₂ CO ₃ (811 mg, 5.87 mmol, 2.00 equiv.), EtI (911 mg , 5.84 mmol, 2.00 equiv.) in DMF (15 mL) was stirred overnight at 80° C., cooled to rt. and extracted with 3×20 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 500 mg (86%) of the title compound as a light yellow oil.

LC-MS: (ES, mass/charge): 199.3. ¹ H NMR (300 MHz, CDCl3) δ 7.29 (m, 1H), 6.70 (m, 2H), 4.08 (q, J=7.0, 7.0, 7.0 Hz, 2H ), 3.92 (s, 3H), 1.40 (t, J=7.0, 7.0 Hz, 3H).

2-Ethoxy-6-fluorobenzoic acid. Solution of the product from the previous step (2.6 g, 13.12 mmol, 1.00 equiv.) and NaOH (2 g, 50.00 mmol, 4.00 equiv.) in MeOH/H ₂ O (20/10 ml ) was stirred overnight at 40°C. The pH of the solution was adjusted to 5 with 1 M HCl. The resulting solution was extracted with 3×50 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 1.9 g (79%) of the title compound as a colorless oil.

LC-MS: (ES, mass/charge): 185.3.

(2-Ethoxy-6-fluorophenyl)methanol. To a solution of the product from the previous step (1.9 g, 10.32 mmol, 1.00 equiv.) and isobutyl chloroformate (2.1 g, 15.38 mmol, 1.50 equiv.) in THF (50 ml) at 0 °C TEA (4.5 ml, 3.00 equiv.) was added. The reaction mixture was stirred for 2 hours at 0° C., then filtered. NaBH ₄ (780 mg, 20.62 mmol, 2.00 equiv.) was added to the filtrate at 0°C. The resulting solution was stirred for 3 hours at room temperature. Then, in the reaction mixture, the reaction was stopped by adding 10 ml of water/ice. The resulting solution was extracted with 3×50 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (2/1) to give 0.7 g (40%) of the title compound as light yellow oils.

¹ H NMR (300 MHz, DMSO) δ 7.27 (td, J=8.3, 8.3, 7.0 Hz, 1H), 6.77 (m, 2H), 4.75 (t, J =5.5, 5.5 Hz, 1H), 4.48 (dd, J=5.5, 1.9 Hz, 2H), 4.06 (q, J=7.0, 7.0, 7 .0 Hz, 2H), 1.35 (t, J=6.9, 6.9 Hz, 3H).

2-(Bromomethyl)-1-ethoxy-3-fluorobenzene. A solution of the product from the previous step (700 mg, 4.11 mmol, 1.00 equiv.), PPh ₃ (2.16 g, 8.24 mmol, 2.00 equiv.) and CBr ₄ (2.7 g, 2.00 equiv.) 00 equiv.) in CH ₂ Cl ₂ (30 ml) was stirred for 2 hours at rt. The resulting solution was extracted with 3×30 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (5/1) to give 0.4 g (42%) of the title compound as a light yellow oil .

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.24 (m, 1H), 6.69 (m, 2H), 4.67 (dd, J=32.8, 1.5 Hz, 2H), 4 .13 (qd, J=7.0, 7.0, 7.0, 2.5 Hz, 2H), 1.48 (td, J=7.0, 6.9, 3.2 Hz, 3H) .

Intermediate E-4: 1-(bromomethyl)-2-(propan-2-yloxy)benzene

[2-(Propan-2-yloxy)phenyl]methanol. To a solution of 2-(hydroxymethyl)phenol (2 g, 16.11 mmol, 1.00 equiv.) in DMF (10 mL) was added successively 2-iodopropane (5.48 g, 32.24 mmol, 2.00 equiv.). ) then Cs ₂ CO ₃ (10.5 g, 32.23 mmol, 2.00 equiv.). The resulting solution was stirred overnight at 85°C. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3×50 ml EtOAc and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/hexane (1/4). This gave the title compound as a light yellow oil (2.1 g, 78%).

1-(Bromomethyl)-2-(propan-2-yloxy)benzene. To a solution of the product from the previous step (3 g, 18.05 mmol, 1.00 equiv.) in CH ₂ Cl ₂ (50 ml) was added successively CBr ₄ (12.84 g, 36.17 mmol, 2.00 equiv. ) and PPh ₃ (9.48 g, 36.14 mmol, 2.00 equiv.) in an ice bath. The resulting solution was stirred for 5 hours at room temperature. The resulting solution was extracted with 3×100 ml CH ₂ Cl ₂ and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/hexane (1/4). This gave the title compound as a light yellow oil (1.6 g, 39%).

The following alkylating agents were reacted with the pyrazoles as disclosed below.

Intermediate E-5 1-(chloromethyl)-2-nitrobenzene

Intermediate E-6 1-bromo-2-(bromomethyl)-benzene

Intermediate E-7 1-(bromomethyl)-2-chlorobenzene

Intermediate E-8 2-(bromomethyl)-1-fluoro-3-nitrobenzene

Intermediate E-9 (2-bromoethyl)benzene

Intermediate E-10 1-(chloromethyl)-2-chlorobenzene

Intermediate E-11 2-(bromomethyl)pyridine

Intermediate E-12 7-(bromomethyl)-1-methyl-lH-indazole

Intermediate E-13 1-bromo-2-methylpropane

Intermediate E-14 4-(bromomethyl)tetrahydropyran

Intermediate D-98: methyl 1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazole-3-carboxylate

To a suspension of methyl 5-phenyl-lH-pyrazole-3-carboxylate (1) (1.0 g, 4.94 mmol) in toluene was added portionwise NaH (60%) (0.394 g, 9.88 mmol) under N ₂ at room temperature and continued stirring for 30 minutes. To the above mixture was added dropwise a solution of 3-chlorobenzyl bromide (0.96 ml, 7.42 mmol) in toluene (3 ml) at 60°C. The reaction mixture was stirred at 110° C. for 16 hours. The mixture was cooled to room temperature and the reaction was stopped with aq. NH ₄ Cl solution. The mixture was separated with EtOAc (100 ml) and the organic layer was separated. The EtOAc layer was washed with brine (2×25 ml) and dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was chromatographed over SiO ₂ (ISCO CombiFlash® Rƒ 200) using a 0-50% gradient of EtOAc in hexanes to give the title compound (1.2 g, 75%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 3.95 (s, 3H), 5.36 (s, 2H), 6.85-6.92 (m, 2H), 6.95-6.99 ( m, 1H), 7.17-7.29 (m, 4H). 7.35-7.48 (m, 3H).

Intermediate D-99: methyl 1-[(2-cyclopropoxyphenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of prom. conn. D-3 (793 mg, 3.41 mmol, 1.00 equiv.) in toluene (10 mL) NaH (164 mg, 6.83 mmol, 2.00 equiv.) was added. The resulting solution was stirred at room temperature. for 30 min., then heated to 60°C. To it was added a solution of prom. conn. E-2 (1 g, 4.40 mmol, 1.30 equiv.) in toluene (10 ml). The resulting solution was stirred at 60°C for 1 hour, then the solution was heated to 110°C and stirred for 6 hours at this temperature. The reaction mixture was then cooled to rt, the reaction was stopped by adding 10 ml of water/ice and was extracted with 3×100 ml of EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo and purified by silica gel column using EtOAc/hexane (1/3) to give 1 g (77%) of the title compound as a yellow oil. LC-MS: (ES, mass/charge): 379.

Intermediate D-100: methyl 1-[(2-chlorophenyl)methyl]-5-(3,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of methyl prom. conn. D-21 (1.0 g, 3.81 mmol, 1.00 equiv.) in toluene (50 mL) was added in portions of NaH (304 mg, 7.60 mmol, 2.00 equiv.) at rt. stirred at rt. for 30 min., then added dropwise prom. conn. E-7 (1.56 g, 7.59 mmol, 2.00 equiv.) with stirring at 60°C. The resulting solution was stirred for 1 hour at 60° C., then heated to 110° C. and stirred for an additional 3 hours. The reaction mixture was then quenched by addition of water/ice. The resulting solution was extracted with 200 ml EtOAc and the combined organic layers were washed with 2×100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:3) with obtaining 800 mg (54%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 387. ¹ H-NMR: (CDCl ₃ , ppm): δ: 7.42-7.29 (m, 1H), 7.29-7.13 (m , 2H), 6.97 (s, 1H), 6.77-6.67 (m, 1H), 6.42 (dd, J=30.5, 2.3 Hz, 3H), 5.55 ( s, 2H), 3.97 (d, J=1.0 Hz, 3H), 3.69-3.60 (m, 6H).

The following substituted pyrazoles were obtained by alkylation using an alkyl halide.

Intermediate D-139: methyl 1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

To a solution of prom. conn. (2,6-dimethoxyphenyl)methanol (1.26 g, ₇ .49 mmol, 1.50 equiv) and then PPh ₃ (1.81 g, 6.90 mmol, 1.30 equiv) was added. Then DIAD (1.75 g, 8.65 mmol, 1.50 equiv.) was added dropwise and the resulting solution was stirred for 16 hours at 25°C. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:19). This gave the title compound as a yellow solid (890 mg, 42%).

Intermediate D-140: methyl 1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

(3-Chloropyridin-2-yl)methanol. To a solution of 3-chloropyridine-2-carboxylic acid (2.1 g, 13.33 mmol, 1.00 equiv) in THF (40 ml) was added Et ₃ N (2.7 g, 26.68 mmol, 2. 00 equiv.) followed by dropwise addition of chloro(propan-2-yloxy)methanone (2.45 g, 19.99 mmol, 1.50 equiv.) with stirring at 0°C. The solution was stirred for 1 hour at room temperature. The solid was removed by filtration. NaBH ₄ (1.53 g, 40.44 mmol, 3.00 equiv.) was added to the filtrate. The resulting solution was stirred for 2 hours at rt, then diluted with 50 ml H ₂ O and extracted with 2×100 ml EtOAc. The combined organic layers were washed with 50 ml saturated NaCl, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:6) to give 0.9 g (47%) of the indicated in the title compound as a colorless oil.

Methyl 1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate. _Prom . conn. D-3 (1.4 g, 6.03 mmol, 1.00 equiv.) and Ph ₃ P (3.1 g, 11.82 mmol, 2.00 equiv.) followed by DIAD (1.00 equiv.) 8 g, 8.91 mmol, 1.50 equiv.) with stirring at 0°C. The resulting solution was stirred for 5 hours at RT, diluted with 30 ml H ₂ O and extracted with 2×50 ml EtOAc. The combined organic layers were washed with 20 ml sat. NaCl, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1:10) to give 1.7 g (80%) of the indicated the title compound as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.35 (dd, J=4.7, 1.5 Hz, 1H), 7.99 (dd, J =8.1, 1.5Hz, 1H), 7.51(s, 1H), 7.45(dt, J=7.7, 1.2Hz, 1H), 7.41(dd, J= 2.6, 1.5 Hz, 1H), 7.36-7.30 (m, 1H), 6.91 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 5 .99 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H).

Intermediate D-141: methyl 1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

Methyl 1-[(4-aminophenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate. To a solution of prom. conn. D-58 (2 g, 4.88 mmol, 1.00 equiv.) in AcOH/H ₂ O (100/40 ml) Zn (1 g, 15.29 mmol, 3.00 equiv.) was added and the resulting solution stirred for 5 hours at 25°C. Solids were collected by filtration. The pH of the solution was adjusted to 7 with (sat.) NaHCO ₃ (aq.) and the resulting solution was extracted with 200 ml of EtOAc. The combined organic layers were concentrated in vacuo to give 1.5 g (81%) of the title compound as a yellow oil.

Methyl 1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate. To a solution of the product from the previous step (1.35 g, 3.56 mmol, 1.00 equiv) in MeOH (50 mL) was added formaldehyde (5 mL, 1.50 equiv) over 30 minutes. NaCNBH ₃ (800 mg, 12.73 mmol, 3.00 equiv.) was added thereto and the resulting solution was stirred for 5 minutes. at 25°C. The resulting solution was extracted with 200 ml EtOAc and the combined organic layers were purified by silica gel chromatography using EtOAc/petroleum ether (1:7) to give 810 mg (56%) of the title compound as a yellow liquid.

Intermediate D-142: methyl 1-[[2-(dimethylamino)-6-fluorophenyl]methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

Intermediate D-142 was obtained from prom. conn. D-133 by performing a restoration sequence using zinc/reductive amination similar to that used to obtain prom. conn. D-141.

Intermediate D-143: methyl 1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-carboxylate

1-[(2-Chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazole-3-carboxylic acid. Solution prom. conn. D-122 (3.2 g, 7.39 mmol, 1.00 equiv.) in AcOH/HCl (15/5 ml) was stirred for 2 hours at 90°C, then cooled, concentrated in vacuo and purified with chromatography on silica gel using EtOAc/petroleum ether (2/1) to give 2 g (82%) of the title compound as a light yellow oil. LC-MS: (ES, mass/charge): 329.0. ¹ H NMR: (300 MHz, DMSO) δ 12.83 (s, 1H), 9.72 (s, 1H), 7.46 (m, 1H), 7.29 (m, 3H), 6.81 (m, 5H), 5.48 (s, 2H).

Methyl 1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazole-3-carboxylate. A solution of the product from the previous step (2 g, 6.08 mmol, 1.00 equiv.) and H ₂ SO ₄ (1 ml) in MeOH (20 ml) was stirred for 2 hours at 65°C. The pH was adjusted to 7 with saturated NaHCO ₃ . The resulting solution was extracted with 3×30 ml EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (2/1) to give 1.7 g (82% ) of the title compound as a white solid. LC-MS: (ES, mass/charge): 343.1. 1H NMR: (400 MHz, DMSO) δ 9.74 (s, 1H), 7.46 (m, 1H), 7.31 (m, 3H), 6.93 (s, 1H), 6.83 ( m, 4H), 5.50 (s, 2H), 3.82 (s, 3H).

Methyl 1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-carboxylate. To a solution of the product from the previous step (1.7 g, 4.96 mmol, 1.00 equiv.), PPh ₃ (2.62 g, 9.99 mmol, 2.00 equiv.) and (oxetan-3-yl )methanol (870 mg, 9.87 mmol, 2.00 equiv.) in THF (30 ml) at -10°C under N ₂ atmosphere was added DTAD (1.82 g, 9.01 mmol, 1.80 equiv. ). The resulting solution was stirred overnight at rt. and extracted with 3×30 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1/3) to give 1.1 g (54%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 413.1.

Intermediate D-144: methyl 5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-7-yl)-1H-pyrazole-3-carboxylate

To a solution of prom. conn. D-95 (600 mg, 1.60 mmol, 1.00 equiv.) in CH ₂ Cl ₂ (15 ml) was added NaH (128 mg, 5.33 mmol, 2.00 equiv.). The solution was stirred for 10 minutes, then SEMCl (664 mg, 2.50 equiv.) was added. The resulting solution was stirred for 16 hours at rt, then the reaction was stopped by adding water and was extracted with 2×100 ml EtOAc. The combined organic layers were washed with 100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified via a silica gel column using EtOAc/petroleum ether (1:2) to give 300 mg (37%) of the title compounds in the form of a yellow oil. LC-MS: (ES, mass/charge): 504.

Intermediate D-145: methyl 5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate

To a solution of prom. conn. D-94 (460 mg, 1.23 mmol, 1.00 equiv.) in CH ₂ Cl ₂ (10 ml) was added NaH (57.5 mg, 2.40 mmol, 2.00 equiv.) at 0°C . The resulting solution was stirred for 30 minutes, then SEMC1 (253 mg, 0.69 mmol, 1.30 equiv.) was added. The resulting solution was stirred for 5 hours at RT, then the reaction was stopped with H ₂ O and was extracted with 3×20 ml of EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography using EtOAc/petroleum ether (1/3) to give 300 mg (48%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 505.1.

Intermediate D-146: methyl-5-(3-cyclopropoxyphenyl)-1-(3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol- 3-carboxylate

To a solution of prom. conn. D-96 (500 mg, 1.29 mmol, 1.00 equiv.) in CH ₂ Cl ₂ (10 ml) was added NaH (62 mg, 2.58 mmol, 2.00 equiv.). The resulting solution was stirred for 30 minutes. at 0° C., then [2-(chloromethoxy)ethyl]trimethylsilane (278 mg, 1.67 mmol, 1.30 equiv.) was added. The resulting solution was stirred for 5 hours at RT, then the reaction was stopped with H ₂ O and was extracted with 3×20 ml of CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by Prep-TLC using EtOAc/petroleum ether (1/3) to give 250 mg (36%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 519.40.

Intermediate D-147: ethyl 1-[(2-chlorophenyl)methyl]-5-phenoxy-1H-pyrazole-3-carboxylate

Ethyl 1-[(2-chlorophenyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate. Solution prom. conn. C-13 (4 g, 17.54 mmol, 1.00 equiv.) and 1,4-diethyl-2-oxobutanedioate (0 mg, 1.30 equiv.) in EtOH (120 mL) were heated to reflux in overnight, then concentrated in vacuo. The crude product was purified by silica gel chromatography using EtOAc/petroleum ether (1:20~1:5) to give 2.8 g (57%) of the title product as a yellow syrup.

Ethyl 1-[(2-chlorophenyl)methyl]-5-(2-nitrophenoxy)-1H-pyrazole-3-carboxylate. A solution of the product from the previous step (2.8 g, 9.97 mmol, 1.00 equiv.), 1-fluoro-2-nitrobenzene (2.8 g, 19.84 mmol, 2.00 equiv.) and K ₂ CO ₃ (2.7 g, 19.57 mmol, 2.00 equiv.) in DMF (20 ml) was stirred overnight at 90°C. The resulting solution was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography using EtOAc/petroleum ether (1:50-1:10) to give 0.8 g (20%) of the title product as a yellow oil.

Ethyl 5-(2-aminophenoxy)-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate. A solution of the product from the previous step (800 mg, 1.99 mmol, 1.00 equiv.) in AcOH/H ₂ O (3:1) (8 ml) was stirred over Zn (600 mg, 9.38 mmol, 5.00 equiv.) for 3 hours at 60°C. Solids were removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using EtOAc/petroleum ether (1:30~1:5) to give 540 mg (73%) of the title product as a yellow solid.

Ethyl 1-[(2-chlorophenyl)methyl]-5-phenoxy-1H-pyrazole-3-carboxylate. To a solution of the product from the previous step (540 mg, 1.45 mmol, 1.00 equiv.) in THF (15 ml) was added tert-butyl nitrite (450 mg, 4.36 mmol, 3.00 equiv.). The resulting solution was stirred for 30 minutes. at 60°C, then concentrated under vacuum. The residue was purified with Prep-TLC (EtOAc:PE=1:3) to give 220 mg (42%) of the title product as a solid.

Intermediate F-1: [1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methanol

Solution prom. conn. D-98 (0.80 g, 2.45 mmol) in anhydrous THF was cooled to 0°C. LiAlH ₄ (0.14 g, 3.67 mmol) was added portionwise to the above mixture and stirring was continued at 0° C. for 1.30 hours. The mixture was quenched with water (0.15 ml) and 30% water. NaOH solution (0.3 ml) at 0°C and continued stirring for 30 minutes. The reaction mixture was filtered, the filter cake was washed with THF (2×10 ml) and the filtrates were combined and evaporated to dryness. The residue was chromatographed over SiO ₂ (ISCO CombiFlash® Rƒ 200) using a 0-40% gradient of EtOAc in DCM to give the title product (0.58 g, 79%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.64-4.81 (d, 2H), 5.31 (s, 2H), 6.35 (s, 1H), 6.86-6.94 ( m, 1H), 6.98-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.26-7.35 (m, 2H), 7.39-7, 46 (m 3H).

The following substituted 3-(hydroxymethyl)pyrazoles were obtained by LiAlH ₄ reduction of the corresponding methyl esters.

Intermediate F-8: [1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methanol

(iii) To a solution of prom. conn. D-28 (5.5 g, 15.41 mmol, 1.00 equiv.) in THF (100 ml) was added dropwise with LiBH ₄ (20 ml) with stirring at 0° C. for 5 minutes. The resulting solution was stirred for 16 hours at room temperature. The reaction mixture was then stopped by adding 5 ml of water, diluted with 200 ml of H ₂ O, extracted with 2×200 ml of EtOAc and the organic layers were combined. The resulting mixture was washed with 1×100 ml of saline, then dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:8). This gave the title compound as a white solid (4.3 g, 85%).

The following substituted 3-(hydroxymethyl)pyrazoles were obtained by reduction of the corresponding methyl esters using LiBH ₄ .

Intermediate F-116: [5-(3-cyclopropoxyphenyl)-1-[[2-(dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methanol

[1-[(2-Aminophenyl)methyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl]methanol. In a 25 ml flask, prom. conn. F-74 [5-(3-cyclopropoxyphenyl)-1-[(2-nitrophenyl)methyl]-1H-pyrazol-3-yl]methanol (350 mg, 0.96 mmol, 1.00 equiv), AcOH ( 7.5 ml), H ₂ O (2.5 ml) and Zn (350 mg, 5.38 mmol, 5.60 equiv.). The resulting mixture was stirred for 3 hours at room temperature. The solids were removed. The resulting solution was extracted with 3×30 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 300 mg (93%) of the title compound as a yellow oil. LC-MS (ES, mass/charge): 336.

[5-(3-Cyclopropoxyphenyl)-1-[[2-(dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methanol. In a 15 ml flask, combine the product from the previous step (300 mg, 0.89 mmol, 1.00 equiv.) MeOH (5 ml), AcOH (0.25 ml), HCHO (358 mg, 11.92 mmol, 4 .00 equiv.) and NaCNBH ₃ (225 mg, 3.57 mmol, 4.00 equiv.). The resulting solution was stirred for 2 hours at 40°C, the reaction was stopped by adding 5 ml of water/ice and was extracted with 3×30 ml of EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by Prep-TLC using EtOAc/hexane (1/1) to give 300 mg (92%) of the title compound as a yellow oil. LC-MS: (ES, mass/charge): 365. ¹ H NMR: (300 MHz, DMSO) δ 7.30 (dd, J=8.8, 7.6 Hz, 1H), 7.22 (td , J=7.6, 7.2, 1.6 Hz, 1H), 7.14 (dd, J=8.1, 1.4 Hz, 1H), 7.00 (m, 2H), 6, 88 (dd, J=6.9, 1.5 Hz, 2H), 6.73 (dd, J=7.7, 1.5 Hz, 1H), 6.42 (s, 1H), 5.35 (s, 2H), 4.46 (s, 2H), 3.67 (dt, J=5.9, 3.1, 3.1 Hz, 1H), 2.55 (s, 6H), 0, 62 (ddd, J=5.9, 3.5, 1.3 Hz, 2H), 0.57 (m, 2H).

The following compounds were prepared by performing a similar reduction sequence with zinc/alkylation.

Intermediate G-1: 3-(bromomethyl)-1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole

To a solution of prom. conn. F-8 (4.3 g, 13.08 mmol, 1.00 equiv.) in CH ₂ Cl ₂ (100 ml) was added CBr ₄ (6.5 g, 1.50 equiv.). This was followed by the dropwise addition of a solution of PPh ₃ (7 g, 26.69 mmol, 2.00 equiv.) in CH ₂ Cl ₂ (10 ml) with stirring at 0° C. for 5 minutes. The resulting solution was stirred for 4 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:5). This gave the title compound as a yellow oil (3.5 g, 68%).

The following substituted 3-(bromomethyl)pyrazoles were prepared by reacting the corresponding (hydroxymethyl)pyrazole with PPh ₃ /CBr ₄ .

Intermediate H-1: methyl 2-([1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl/methoxy)-2-methylpropanoate

To a solution of prom. conn. F-1 (0.288 g, 0.964 mmol) in DMF was added in portions of NaH (60%) (0.077 g, 1.93 mmol) under N ₂ at room temperature and stirring continued for 30 minutes. The mixture was cooled to 0° C. and methyl 2-bromo-2-methylpropanoate (0.16 ml, 1.25 mmol) was added dropwise followed by NaI (0.143 g, 0.964 mmol). The reaction mixture was gradually warmed to room temperature and stirred overnight. At the end of this period, aq. NH ₄ Cl solution and the mixture was separated with EtOAc (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The combined EtOAc layers were washed with brine and dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was chromatographed over SiO ₂ (ISCO CombiFlash® Rƒ 200) using a 0-50% gradient of EtOAc in hexanes to give the title product as an oil (0.068 g, 38%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.56 (s, 6H). 3.68 (s, 3H), 4.58 (s, 2H), 5.25 (s, 2H), 6.45 (s, 1H), 6.87-6.93 (m, 1H), 7 .00 (s, 1H), 7.16-7.22 (m, 2H), 7.26-7.34 (m, 2H), 7.34-7.42 (m, 3H).

The following substituted pyrazolecarboxylic acid esters were prepared from the synthesis of the corresponding (hydroxymethyl)pyrazole via the Williamson ether synthesis reaction using BrC(CH ₃ ) ₂ COOMe.

Received the following esters of 2-hydroxy-2-methylbutanoic acid.

Methyl 2-hydroxy-2-methylbutanoate. To a solution of 2-hydroxy-2-methylbutanoic acid (3.0 g, 25.40 mmol, 1.00 equiv.) in MeOH (100 ml) was added dropwise H ₂ SO ₄ (3 ml) with stirring at 0°C . The resulting solution was heated to reflux for 16 hours, cooled, concentrated in vacuo, diluted with 200 ml EtOAc, washed with 1×100 ml (sat.) NaHCO3 (aq.), dried over Na ₂ SO ₄ and concentrated in vacuo to give 780 mg (23%) of the title compound as a colorless oil.

Methyl-(2R)-2-hydroxy-2-methylbutanoate. To a solution of (2R)-2-hydroxy-2-methylbutanoic acid (1.0 g, 8.47 mmol, 1.00 equiv.) in MeOH (50 ml) was added dropwise SOCl ₂ (2.0 g, 2, 00 equiv.) with stirring at 0°C. The resulting solution was heated to reflux temperature for 16 hours, then concentrated under vacuum, diluted with 100 ml of CH ₂ Cl ₂ . The mixture was dried over Na ₂ SO ₄ and concentrated in vacuo to give 700 mg (63%) of the title compound as a colorless oil. ¹ H-NMR: (300 MHz, CDCl ₃ ) δ: 3.79 (s, 3H), 3.04 (s, 1H), 1.89-1.61 (m, 2H), 1.41 (s , 3H), 0.88 (t, J=7.4 Hz, 3H).

Methyl-(2S)-2-hydroxy-2-methylbutanoate. SOCl ₂ (1.03 mg, 0.01 mmol , 2.00 equiv.) with stirring at 0°C. The resulting solution was stirred for 16 hours at 60°C, then concentrated under vacuum, diluted with 200 ml CH ₂ Cl ₂ , washed with 1×100 ml (sat.) NaHCO 3 (aq.) and evaporated under reduced pressure. The solid that formed was dried in an oven under reduced pressure to give 400 mg (72%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 132. ¹ H NMR (DMSO) δ: 5.10 (s, 1H), 3.62 (s, 3H), 1.73-1.44 (m, 2H), 1.24 (s, 3H), 0.78 (t, J=7.4 Hz, 3H).

The following substituted pyrazolecarboxylic acid esters were prepared from the synthesis of the corresponding (bromomethyl)pyrazole via the Williamson ether synthesis reaction using HO-C(CH ₃ ) ₂ COOMe:

Intermediate H-114: methyl 2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

tert-Butyl-2-([1-[(2-chlorophenyl)methyl]-5-(4-bromothien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate. To a solution of tert-butyl 2-hydroxy-2-methylpropanoate (2.14 g, 13.36 mmol, 3.00 equiv.) in THF (50 ml) was added parts of NaH (535 mg, 13.38 mmol, 3, 00 equiv.) at 0°C. The mixture was stirred at 0° C. for 20 minutes. Prom was added to it. conn. G-23 (2 g, 4.48 mmol, 1.00 equiv.) at 0°C and Bu ₄ NI (1.0 g, 2.72 mmol, 0.50 equiv.). The resulting solution was stirred for 16 hours at rt, then the reaction was stopped by adding water/ice. The resulting solution was extracted with 500 ml EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:2). This gave the title compound as a yellow oil (400 mg, 17%).

Methyl 2-([5-(4-bromothien-2-yl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate. Aq. HCl (1 ml) with stirring at rt. The resulting solution was stirred for 3 hours at 65°C, concentrated under vacuum and diluted with 100 ml EtOAc. The pH of the solution was adjusted to 7-8 with (sat.) NaHCO ₃ (aq.). The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This gave the title compound as a yellow oil (350 mg, 95%).

Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate. To a solution of the product from the previous step (350 mg, 0.72 mmol, 1.00 equiv.) in dioxane (10 ml) was gradually added Cs ₂ CO ₃ (473 mg, 1.45 mmol, 2.00 equiv.), precatalyst 2nd generation XantPhos (322 mg, 0.36 mmol, 0.50 equiv) and cyclopropanol (168 mg, 2.89 mmol, 4.00 equiv). The final reaction mixture was irradiated with microwave radiation for 1 hour at 85°C. The resulting solution was diluted with 100 ml EtOAc. The resulting mixture was washed with 2×100 ml of saline. The mixture was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:2). This gave the title compound as a yellow oil (150 mg, 45%).

Intermediate H-115: methyl 2-([5-(3-aminophenyl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of prom. conn. H-95 (400 mg, 0.90 mmol, 1.00 equiv.) in AcOH/H ₂ O (10/1 mL) was added in portions of Zn (400 mg, 6.15 mmol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. Solids were removed by filtration. The pH value of the solution was adjusted to 7-8 with sat. _NHCO3 . The resulting solution was extracted with 100 ml EtOAc and the organic layers were combined, washed with 2x200 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo.

The residue was purified with Prep-TLC using DCM/MeOH (30:1) to give 230 mg (62%) of the title product as a yellow oil.

Intermediate H-116: methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(2-methylpropanamido)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

Solution prom. conn. H-115 (200 mg, 0.48 mmol, 1.00 equiv), HATU (276 mg, 0.73 mmol, 1.50 equiv), 2-methylpropanoic acid (130 mg, 1.48 mmol, 3 00 equiv.) and DIEA (187 mg, 1.45 mmol, 3.00 equiv.) in DMF (20 mL) were stirred overnight at rt. , then diluted with 200 ml EtOAc, washed with 2×100 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by Prep-TLC using DCM/MeOH (30:1) to give 155 mg (66%) of the title product as a yellow solid.

Intermediate H-117: methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylsulfanyl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of prom. conn. H-115 (700 mg, 1.69 mmol, 1.00 equiv.) in MeCN (10 mL), dimethyl disulfide (319 mg, 3.39 mmol, 2.00 equiv.) was added. The resulting mixture was heated at 60°C for 1 hour, then cooled to rt. Then tert-butyl nitrite (350 mg, 3.40 mmol, 2.00 equiv.) was added dropwise with stirring and the resulting solution was stirred for 3 hours at 60°C, then diluted with 200 ml EtOAc, washed with 2 ×100 ml of saline, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:2). This resulted in 300 mg (40%) of the title product as a yellow oil.

Intermediate H-118: methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methanesulfonylphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of prom. conn. H-117 (300 mg, 0.67 mmol, 1.00 equiv.) in MeOH/H ₂ O (10/5 mL) was added in portions of K ₂ S ₂ O ₈ (233 mg, 1.53 mmol, 1.00 equiv.) at r.t. The resulting solution was stirred for 2 hours, then diluted with 200 ml EtOAc, washed with 2×100 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:3). This resulted in 180 mg (58%) of the title product as a yellow solid.

Intermediate H-119: methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methanesulfonamidophenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of prom. conn. H-115 (200 mg, 0.48 mmol, 1.00 equiv), pyridine (75 mg, 0.95 mmol, 2.00 equiv), and DMAP (6 mg, 0.05 mmol, 0.10 equiv) .) in DCM (10 ml) was added dropwise methanesulfonyl chloride (83 mg, 0.72 mmol, 1.50 equiv.) with stirring at 0°C. The resulting solution was stirred overnight at rt, then diluted with 100 ml DCM, washed with 2×100 ml brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:4). This resulted in 100 mg (42%) of the title product as a yellow oil.

Intermediate H-120: methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of prom. conn. H-115 (200 mg, 0.48 mmol, 1.00 equiv.) in MeOH (10 mL) was added paraformaldehyde (107 mg, 2.43 mmol, 5.00 equiv.) followed by MeONa (0.00 equiv.) dropwise. 45 ml, 5.00 equiv., 5.4 M) with stirring at room temperature. The resulting solution was stirred for 2 hours at 60°C, then cooled to 0°C. NaBH ₄ (92 mg, 2.43 mmol, 5.00 equiv.) was added and the solution was stirred for 1 hour at 60°C, then cooled, diluted with 100 ml EtOAc, washed with 2×50 ml brine , dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:4). This resulted in 100 mg (48%) of the title product as a yellow oil.

Intermediate H-121: methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate

Methyl 2-ethyl-2-hydroxybutanoate. To a solution of 2-ethyl-2-hydroxybutanoic acid (2.0 g, 15.13 mmol, 1.00 equiv.) in MeOH (100 ml) was added dropwise H ₂ SO ₄ (3 ml) with stirring at r.t. . The resulting solution was heated to reflux temperature for 16 hours, then concentrated under vacuum, diluted with 200 ml EtOAc, washed with 2×100 ml sat. NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 800 mg (36%) of the title product as a colorless oil.

Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate. To a solution of methyl 2-ethyl-2-hydroxybutanoate (371 mg, 2.54 mmol, 2.00 equiv.) in DMF/THF (7/7 ml) was added NaH (100 mg, 4.17 mmol, 2.00 equiv.) at 0°C for 30 min. NaI (140 mg) and prom. conn. G-1 (500 mg, 1.28 mmol, 1.00 equiv.). The resulting solution was stirred for 16 hours at room temperature. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:10). The collected fractions were combined and concentrated in vacuo. This resulted in 210 mg (38%) of the title product as a white liquid.

Intermediate H-122: methyl-(2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy) -2-methylbutanoate

Methyl-(2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate. To a solution of methyl (2R)-2-hydroxy-2-methylbutanoate (250 mg, 1.89 mmol, 2.00 equiv.) in THF (20 ml) was added parts of NaH (76 mg, 1.90 mmol, 2, 00 equiv.) at 0°C. The mixture was stirred at 0° C. for 20 minutes, then prom. conn. F-10 (400 mg, 0.94 mmol, 1.00 equiv.) at 0°C, Bu4NI (200 mg, 0.54 mmol, 0.50 equiv.). The resulting solution was stirred for 16 hours at rt, then the reaction was stopped by adding water/ice. The resulting solution was extracted with 100 ml ethyl acetate and the combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by Prep-TLC using EtOAc/petroleum ether (1:1) to give 160 mg (36%) of the indicated in title compound as a yellow solid. LC-MS: (ES, mass/charge): 475.

The following substituted pyrazolecarboxylic acid esters were prepared from the synthesis of the corresponding (bromomethyl)pyrazole via the Williamson ether synthesis reaction using HO—C(CH ₃ )(Et)COOMe.

Intermediate H-133: methyl-2-([1-[2-(azetidin-1-yl)phenyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl ]methoxy)-2-methylpropanoate

Methyl-2-([1-(2-bromophenyl)-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- methyl propanoate (200 mg, 0.40 mmol, 1.00 equiv) L-Proline (46 mg, 0.40 mmol, 1.00 equiv), CuI (38 mg, 0.20 mmol, 0.50 equiv) ), K ₂ CO ₃ (166 mg, 1.20 mmol, 3.00 equiv.), azetidine (69 mg, 1.21 mmol, 3.00 equiv.) and DMSO (10 ml). The resulting solution was stirred overnight at 70°C. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3×20 ml EtOAc and the organic layers were combined and dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by Prep-TLC using EtOAc/petroleum ether (1/3). This resulted in 50 mg (26%) of the title compound as a light yellow oil. LC-MS: (ES, mass/charge): 474. ¹ H NMR: (300 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.62 (d, J=8.4 Hz, 1H) , 7.34 (s, 1H), 7.24 (m, 2H), 7.07 (dd, J=7.8, 1.5 Hz, 1H), 6.76 (s, 1H), 6, 69 (td, J=7.6, 7.5, 1.3 Hz, 1H), 6.45 (dd, J=8.2, 1.3 Hz, 1H), 4.63 (s, 2H) , 4.25 (q, J=7.3, 7.3, 7.3 Hz, 2H), 3.79 (s, 3H), 3.58 (dq, J=24.9, 7.4, 7.3, 7.3 Hz, 4H), 2.10 (p, J=7.3, 7.3, 7.3, 7.3 Hz, 2H), 1.56 (s, 6H), 1 .34 (q, J=8.2, 8.2, 7.2 Hz, 3H).

Intermediate H-134: methyl-2-([1-[2-(azetidin-1-yl)phenyl]-5-[3-(2,2-dimethylpropoxy)phenyl]-1H-pyrazol-3-yl] methoxy)-2-methylpropanoate

In a 30 ml sealed tube, prom. conn. H-4 (200 mg, 0.39 mmol, 1.00 equiv.), L-proline (44 mg, 0.38 mmol, 1.00 equiv.), CuI (40 mg, 0.21 mmol, 0.00 equiv.), 50 equiv.), K ₂ CO ₃ (160 mg, 1.16 mmol, 3.00 equiv.), azetidine (66 mg, 1.16 mmol, 3.00 equiv.) and DMSO (10 ml). The resulting solution was stirred overnight at 70°C, cooled and extracted with 3×15 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by prep-TLC using EtOAc/petroleum ether (1/3) to give 70 mg (37%) of the title compound as a light yellow oil. LC-MS: (ES, mass/charge): 492.30. ¹ H NMR: (300 MHz, DMSO) δ 7.28 (ddd, J=8.5, 7.4, 1.6 Hz, 1H), 7.20 (t, J=7.9, 7.9 Hz, 1H), 6.98 (ddd, J=9.9, 7.2, 1.5 Hz, 2H), 6.84 (m, 2H), 6.69 (m, 2H), 6.51 (dd, J=8.3, 1.3 Hz, 1H), 4.44 (s, 2H), 3.71 (s, 3H), 3.50 (m, 2H), 3.42 (m, 2H), 2.07 (m, 2H), 1.45 (s, 6H), 0.94 (s, 9H).

The following amino-substituted aryl compounds were prepared using similar copper (I) mediated coupling procedures.

Intermediate H-156: methyl 2-([1-(2-cyanophenyl)-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl/methoxy)-2-methylpropanoate

To a solution of prom. conn. H-46 (150 g, 309.04 mmol, 1.00 equiv.) and Zn(CN) ₂ (72 mg, 0.62 mmol, 2.00 equiv.) in DMF (15 mL) were added in portions of Pd(PPh ₃ ) ₄ (36 mg, 0.03 mmol, 0.10 equiv.) at RT The resulting solution was stirred for 16 hours at 100°C, diluted with 100 ml EtOAc, washed with 2×50 ml (sat.) FeSO ₄ (aq.), dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:2). This resulted in 100 mg of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 432.

Chromatographic Procedures

All chromatographic procedures were performed on a 2#-AnalyseHPLC-SHIMADZU(HPLC-10) instrument with detection at 254/220 nm. Columns used for purification include the following.

"Xselect": XSelect CSH Prep C18 OBD column, 19*250 mm, 5 µm.

"XBridge": column XBridge Prep C18 OBD, 19*150 mm, 5 µm.

Examples

The present invention is further illustrated with the help of the following examples.

Example 1: 2-([1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

To a solution of prom. conn. H-1 (0.068 g, 0.170 mmol) in THF:MeOH:H ₂ O (2:1:1) (8 ml) was added LiOH*H ₂ O (0.035 g, 0.85 mmol) at rt. and continued stirring for an additional 3 hours. Then the solvent was evaporated and water (2 ml) was added to the residue and acidified with 1 M citric acid. The mixture was extracted with EtOAc (25 ml) and washed with water (10 ml) and then brine (10 ml). The EtOAc layer was dried over Na ₂ SO ₄ and the solvent was removed by evaporation. The crude product was chromatographed over SiO ₂ (ISCO CombiFlash® Rƒ 200) using a 0-30% MeOH gradient in DCM to give the title product as a white solid (0.032 g). ¹ HNMR(CDCl ₃ ): δ 1.56(s, 6H), 4.61(s, 2H), 5.34(s, 2H), 6.38(s, 1H), 6.87-6, 97(m, 1H), 7.04(s, 1H), 7.18-7.24(m, 2H), 7.26-7.35(m, 2H), 7.35-7.45( m, 3H).

Examples 2-50 were prepared in the same way as described in example 1.

Examples 51-74 were obtained using the methods disclosed in these schemes.

Example 75: 2-([1-[(2-chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

2-[(5-[[(tert-Butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl)methoxy)-2-methylpropanoic acid was obtained from industrial . conn. H-93 using the procedure of Example 1. This gave 200 mg as a yellow oil.

2-([1-[(2-Chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. To a solution of the product from the previous step (200 g, 400.01 mmol, 1.00 equiv.) in DCM (10 ml) was added dropwise TFA (5 ml) with stirring at rt. The resulting solution was stirred for 1 hour then concentrated in vacuo. The crude product (150 mg) was purified with Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHFMADZU(HPLC-10)): column, SunFire C18 OBD Prep column, 0.1 nM, 5 μM, 19 mm × 150 mm, mobile phase, Waters (0.1% TFA) and ACN (61.0% ACN to 74.0% within 6 min.); detector, UV 254 nm) to give 19.2 mg of the title product as a white solid.

¹ H-NMR (300 MHz, MeOD) δ 1.50 (6H, s), 4.48 (2H, s), 5.34 (2H, d), 6.18 (1H, s), 6.68 -6.95 (4H, m), 7.11-7.30 (4H, m), 7.33-7.43 (1H, m).

The following examples were prepared using the indicated schemes.

Example 78 was intentionally not used.

Example 79: 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

(i) 2-([1-[(2-Chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. A solution of methyl 2-([5-(3-benzyloxyphenyl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate in a mixture of acetic acid and conc. HCl (8 ml) (3:1, v/v) was heated at 90° C. for 6 hours. At the end of this period, the reaction mixture was evaporated to dryness and the residue was subjected to chromatography over SiO ₂ using a 0-20% gradient MeOH in DCM to give the title product. ¹ HNMR (CDCl ₃ ): δ 1.55 (s, 6H), 4.61 (s, 2H), 5.40(s, 2H), 6.38 (s, 1H), 6.74-6, 83(m, 4H), 7.18-7.35(m, 4H).

Example 80: 2-([1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

(i) Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate. 4 drops of conc. . H2SO4 and the solution heated at reflux for 16 hours. The product was evaporated to dryness and the residue was chromatographed over SiO ₂ using a 0-25% MeOH gradient in DCM to give the title product.

(ii) Methyl 2-([1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate. To a solution of methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate (0.170 g, 0.410 mmol) in DMF [oxetan-3-yl]methyl-4-methylbenzenesulfonate (0.149 g, 0.615 mmol) and K ₂ CO ₃ (0.113 g, 0.820 mmol) were added at room temperature.

The mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with EtOAc (20 ml × 2). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was chromatographed over SiO ₂ using a 0-100% EtOAc in hexane gradient to give the title product. ¹ HNMR (CDCl ₃ ): δ 1.54 (s, 6H), 3.33-3.36 (m, 1H), 3.77 (s, 3H), 3.97 (d, 2H), 4, 30 (t, 2H), 4.56 (s, 2H), 4.84 (t, 2H), 5.40 (s, 2H), 6.53 (s, 1H), 6.77-6.90 (m, 4H), 7.19-7.37 (m, 4H).

(iii) 2-([1-[(2-Chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid was prepared similarly as described in step iv of example 1 to give the title product (20 mg). ¹ HNMR (CDCl ₃ ): δ 1.55 (s, 6H), 3.34-3.74 (m, 1H), 3.98 (d, 2H), 4.49 (t, 2H), 4. 63 (s, 2H), 4.83 (t, 2H), 5.43 (s, 2H), 6.44 (s, 1H), 6.76-6.93 (m, 4H), 7.20 -7.37 (m, 4H).

Example 81 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methyl-N-methylsulfonylpropanamide.

To a solution of Example 14 (2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid) (0.08 g, 0.192 mmol) in CH ₃ CN were added CDI (0.047 g, 0.288 mmol) and methanesulfonamide (0.022 g, 0.23 mmol) at rt. The mixture was stirred at rt. within 16 hours the Solvent was evaporated and the residue was subjected to chromatography over SiO ₂ using a 0-20% MeOH gradient in DCM to obtain specified in the title product. ¹ HNMR (CDCl ₃ ): δ 1.55 (s, 6H), 3.21 (s, 3H), 3.67 (s, 3H), 4.58 (s, 2H), 5.48 (s, 2H), 6.36 (s, 1H), 6.75-6.92 (m, 4H), 7.18-7.35 (m, 4H).

Example 82: Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate.

Example 82 was prepared in the same way as described in example 1, with the exception of stage iv. ¹ HNMR (CDCl ₃ ): δ 1.54 (s, 6H), 3.65 (s, 3H), 3.77 (s, 3H), 4.56 (s, 2H), 5.37 (s, 2H), 6.53 (s, 1H), 6.71-6.78 (m, 2H), 6.85-6.90 (m 2H), 7.10-7.13 (m, 1H), 7.21-7.27 (m, 2H), 7.51-7.53 (m 1H).

Examples 83-100 were deliberately not used.

The following examples were prepared using the indicated schemes.

Examples 120/121: (2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid and (2R )-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid.

Ethyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate. To a solution of prom. conn. G-1 (700 mg, 1.79 mmol, 1.00 equiv.) in THF (10 ml) under N ₂ , NaH (200 mg, 8.33 mmol, 3.00 equiv.) was added. The solution was stirred for 10 minutes. at 0°C. To this was added methyl 2-hydroxy-2-methylbutanoate (700 mg, 5.30 mmol, 3.00 equiv.), Bu4NI (330 mg, 0.50 equiv.). The resulting solution was stirred for 4 hours at room temperature. The reaction was stopped by adding 1 ml of water. The resulting solution was diluted with 20 ml H ₂ O, extracted with 2×30 ml EtOAc and the organic layers were combined. The resulting mixture was washed with 20 ml of saturated NaCl, then dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was passed through a silica gel column using EtOAc/petroleum ether (1:5). This gave the title compound as a yellow oil (300 mg, 38%).

(vi) Chiral resolution of ethyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate. The crude product of step v was purified with chiral Prep-HPLC using the following conditions (Prep-HPLC-004): column, Chiralpak IC, 2*25 cm, 5 µm; mobile phase, hex- and ethanol- (retention of 2.0% ethanol - for 23 min.); detector, UV 254/220 nm. Received 100 mg of product with Alpha (25°C, 0.05 mol/l, MeOH). As a result, ethyl-(2,5)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate was obtained in as a colorless oil (100 mg, 36%) and ethyl-(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy) -2-methylbutanoate as a colorless oil (100 mg, 36%).

(vii) (2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid was prepared from ethyl-( 2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate in the same manner as described in step iv of Example 1. ¹ H-NMR (400 MHz, MeOD) δ 7.45-7.38 (m, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.31-7.29 (m, 1H), 7.29-7.24 (m, 1H), 6.83 (dd, J=2.5, 1.6 Hz, 1H), 6.80-6.72 (m, 1H), 6 .56 (s, 1H), 5.44 (s, 2H), 4.59 (s, 2H), 3.69 (s, 3H), 1.89 (qd, J=7.2, 5.0 Hz, 2H), 1.51 (s, 3H), 0.98 (t, J=7.5 Hz, 3H). LC-MS (ES, mass/charge): 429.

(viii) (2R)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid was prepared from ethyl-( 2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate in the same manner as described in step iv of Example 1. ¹ H-NMR (400 MHz, MeOD) δ 7.45-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.31-7.29 (m, 1H), 7.29-7.24 (m, 1H), 6.97 (ddd, J=8.4, 2.6, 0.9 Hz, 1H), 6.93 (dt, J=7.6, 1 .2 Hz, 1H), 6.83 (dd, J=2.6, 1.6 Hz, 1H), 6.81-6.72 (m, 1H), 6.56 (s, 1H), 5 .44 (s, 2H), 4.59 (s, 2H), 3.69 (s, 3H), 1.89 (qd, J=7.2, 4.9 Hz, 2H), 1.51 ( s, 3H), 0.98 (t, J=7.5 Hz, 3H). LC-MS (ES, mass/charge): 429.

Alternative synthesis of examples 120/121: (2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid and (2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid.

Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate. To a solution of methyl 2-hydroxy-2-methylbutanoate (780 mg, 5.90 mmol, 1.00 equiv.) in THF (50 ml) under N ₂ was added parts of NaH (236 mg, 5.90 mmol, 1.00 equiv.) 00 equiv.) at 0°C. The mixture was stirred at 0° C. for 30 minutes, then prom. conn. G-1 (1.16 g, 2.96 mmol, 0.50 equiv.) and Bu ₄ NI (600 mg, 1.63 mmol, 0.50 equiv.) at 0°C. The resulting solution was stirred for 16 hours at rt, then the reaction was stopped by adding water/ice. The resulting solution was diluted with 200 ml EtOAc, washed with 2×100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified with Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC- 10)): column, XBridge Prep OBD C18 column, 30×150 mm, 5 µm; mobile phase, water (0.1% FA) and ACN (55.0% ACN to 79.0% within 7 minutes); detector, UV 254/220 nm, to give 200 mg (8%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 443.

Chiral separation of (2R)- and (2S)-methyl-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate . Racemic methyl ester (200 mg, 0.45 mmol, 1.00 equiv.) was separated into enantiomers by chiral Prep-HPLC using the following conditions: column: Chiralpak IC, 2*25 cm, 5 μm; mobile phase A: Hex--HPLC; mobile phase B: EtOH--HPLC; flow rate: 20 ml/min; gradient: 2V to 2V over 24 min; 220/254 nm; RT1:18.171; RT2:20.742 to give 80 mg (40%) methyl-(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy )-2-methylbutanoate and 70 mg (35%) methyl-(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy )-2-methylbutanoate, both as colorless oils.

Alternative synthesis of methyl-(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

Methyl-(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate. To a solution of methyl (2S)-2-hydroxy-2-methylbutanoate (400 mg, 3.03 mmol, 1.00 equiv.) in THF (20 ml) was added parts of NaH (122 mg, 3.05 mmol, 1.00 equiv.) 00 equiv.) at 0°C. The mixture was stirred at 0° C. for 10 min., then prom. conn. G-1 (400 mg, 1.02 mmol, 0.34 equiv.) and Bu ₄ NI (200 mg, 0.54 mmol, 0.50 equiv.) at 0°C. The resulting solution was stirred for 16 hours at rt, the reaction was stopped by adding water/ice and was extracted with 100 ml of EtOAc. The combined organic layers were washed with 1×100 ml brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by Prep-TLC using EtOAc/petroleum ether (1:3) to give 150 mg (11%) of the indicated in the title compound as a colorless oil. LC-MS: (ES, mass/charge): 443.

Example 120: (2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid.

To a solution of methyl-(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate (70 mg, 0 .16 mmol, 1.00 equiv.) in THF/H ₂ O/MeOH (4/2/2 mL) was added in portions of LiOH (23 mg, 0.96 mmol, 6.00 equiv.) at rt. The resulting solution was stirred for 2 hours at room temperature. The pH was adjusted to 3-4 with conc. HCl. The resulting solution was extracted with 100 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, XBridge Prep OBD C18 column, 30×150 mm , 5 µm; mobile phase, water (0.1% FA) and ACN (40.0% ACN to 75.0% over 7 minutes); detector, UV 254/220 nm, to give 40 mg (59%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 429. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 7.50-7.22 (m, 4H), 7.02-6.84 (m, 3H), 6.78-6.69 (m, 1H), 6.45 (s, 1H), 5.38 (s, 2H), 4.41 (d, J=2.2Hz, 2H), 3.69(s, 3H), 1.87-1.61(m, J=7.1Hz, 2H), 1.36(s, 3H), 0, 85 (t, J=7.4 Hz, 3H).

Example 121: (2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid.

To a solution of methyl-(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate (80 mg, 0 18 mmol, 1.00 equiv.) in THF/H ₂ O/MeOH (4/2/2 mL) was added in portions of LiOH (26 mg, 1.09 mmol, 6.00 equiv.) at rt. stirred for 2 hours at room temperature. The pH was adjusted to 3-4 with conc. HCl. The resulting solution was extracted with 100 ml EtOAc and the organic layers were combined, dried over Na ₂ SO ₄ , concentrated under vacuum and purified using Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, column XBridge Prep OBD С18, 30×150 mm, 5 µm; mobile phase, water (0.1% FA) and ACN (40.0% ACN to 75.0% over 7 minutes); detector, UV 254/220 nm, to give 46.3 mg (60%) of the title compound as a colorless oil. LC-MS: (ES, mass/charge): 429. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 12.61 (s, 1H), 7.49-7.22 (m, 4H), 7.02-6.84 (m, 3H), 6.78-6.69 (m, 1H), 6.46 (s, 1H), 5.38 (s, 2H), 4.41 (d, J=2.2Hz, 2H), 3.69(s, 3H), 1.84-1.61(m, J=7.6Hz, 2H), 1.36(s, 3H), 0, 85 (t, J=7.4 Hz, 3H).

The following examples were prepared using Scheme III.

The following examples were prepared using the indicated schemes.

Example 143: (3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoic acid.

(ii) ([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methyl)triphenylphosphonium bromide. To a solution of prom. conn. G-1 (2.4 g, 6.13 mmol, 1.00 equiv.) in toluene (20 ml) was added PPh ₃ (2.4 g, 9.15 mmol, 1.50 equiv.) at room temperature. The resulting solution was stirred for 3 hours at 110°C. Solids were collected by filtration. The solid was dried in an oven under reduced pressure. This gave the title compound as a white solid (2.2 g, 55%).

(iii) Methyl-(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoate. To a solution of ([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methyl)triphenylphosphonium bromide (500 mg, 0.76 mmol, 1.00 equiv.) in THF (20 ml) was added methyl 2,2-dimethyl-3-oxopropanoate (200 mg, 1.54 mmol, 2.00 equiv.). This was followed by the addition of parts of NaH (50 mg, 1.25 mmol, 2.00 equiv.) at 0°C. The resulting solution was stirred for 16 hours at room temperature, then the reaction was stopped by adding water/ice. The resulting solution was diluted with 100 ml of EtOAc, then washed with 2×50 ml of saline. The mixture was dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was subjected to Prep-TLC using EtOAc/petroleum ether (1:2). This gave the title compound as a colorless oil (125 mg, 38%).

(iv) (3E)-4-[1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoic acid was prepared similarly as described in step iv of Example 101 using methyl-(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2, 2-dimethylbut-3-enoate as starting material. ¹ H-NMR (400 MHz, MeOD) δ 1.42 (s, 6H), 3.69 (s, 3H), 5.43 (s, 2H), 6.49 (d, 1H), 6.56 -6.68 (m, 2H), 6.71-6.79 (m, 1H), 6.84 (dd, 1H), 6.90-7.06 (m, 2H), 7.23-7 .47 (m, 5H). LC-MS (ES, mass/charge): 411.

Example 144 4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoic acid

(i) Methyl-(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoate was prepared as in steps i-iii of example 143.

(ii) Methyl 4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoate. To a solution of methyl-(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoate (60 mg, 0.14 mmol, 1.00 equiv.) in EtOAc/MeOH (10/10 ml) was added Pd/C (20 mg). The resulting solution was stirred for 3 hours under H ₂ atmosphere at room temperature. Solids were removed by filtration. The resulting mixture was concentrated under vacuum. The residue was purified with Prep-TLC using 20:1 CH ₂ Cl ₂ : MeOH. This gave the title compound as a colorless oil (40 mg, 66%).

(iii) 4-[1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoic acid was prepared analogously as described in step iv of Example 101 using methyl 4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoate as starting material. ¹ H-NMR (400 MHz, MeOD) δ 1.26-1.38 (m, 6H), 1.98 (s, 2H), 2.69 (s, 2H), 3.68 (s, 3H) , 5.41 (s, 2H), 6.35 (s, 1H), 6.69 (dd, 1H), 6.81 (dd, 1H), 6.87-7.00 (m, 2H), 7.23-7.36 (m, 3H), 7.38-7.45 (m, 1H). LC-MS (ES, mass/charge): 413.

Examples 145-149 were deliberately not used.

Example 150: 2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

To a solution of prom. conn. H-64 (120 mg, 0.26 mmol, 1.00 equiv.) in THF/H ₂ O/MeOH (8/4/4 mL) was added in portions of LiOH (37 mg, 1.54 mmol, 6.00 equiv. .) at room temperature. The resulting solution was stirred for 2 hours at room temperature. The pH was then adjusted to 3-4 with aq. HCl. The resulting solution was extracted with 100 ml EtOAc and the combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product (100 mg) was purified by Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase, water (0.1% FA) and ACN (38.0% ACN to 65.0% over 7 minutes); detector, UV 254/220 nm, to give 42 mg (36%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 453. ¹ H-NMR: (DMSO) δ: 12.70 (s, 1H), 8.09 (d, J=0.9 Hz, 1H), 7 .80 (dd, J=8.4, 0.8 Hz, 1H), 7.70 (t, J=1.1 Hz, 1H), 7.48-7.37 (m, 1H), 7, 36-7.23 (m, 2H), 7.14 (dd, J=8.4, 1.3 Hz, 1H), 6.86-6.75 (m, 1H), 6.55 (s, 1H), 5.47 (s, 2H), 4.46 (s, 2H), 4.41 (q, J=0.9 Hz, 2H), 1.42 (s, 6H), 1.36 ( t, J=0.6 Hz, 3H).

Example 151 Sodium 2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

Solution of 2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid (Example 150 , 50 mg, 0.11 mmol, 1.00 equiv.) and NaOH (18 mg, 0.45 mmol, 4.00 equiv.) in MeOH/H ₂ O (5/2 ml) were stirred for 3 h. at rt, then purified with Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, XBridge Shield RP18 OBD column, 5 µm, 19*150 mm; mobile phase, water (10 mmol/l NH4HCO3) and MeOH- (15.0% MeOH- to 95.0% within 7 minutes); detector, UV 254/220 nm, to give 20.9 mg (40%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 453.00. ¹ H NMR (300 MHz, DMSO) δ 8.07 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.65 (s, 1H), 7.41 (m, 1H), 7.28 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.79 (m, 1H), 6.56 (s, 1H), 5.46 ( s, 2H), 4.49 (s, 2H), 4.37 (q, J=7.2, 7.2, 7.2 Hz, 2H), 1.34 (d, J=17.1 Hz , 9H).

Example 152: 2-([5-(3-cyclopropoxyphenyl)-1-(1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

(i) 2-([5-(3-Cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy )-2-methylpropanoic acid. Solution prom. conn. H-76 (100 mg, 0.17 mmol, 1.00 equiv.) and LiOH (20 mg, 0.84 mmol, 4.00 equiv.) in THF/H ₂ O (4/1 mL) were stirred for 2 hours at room temperature, then cooled to 0°C. The pH was adjusted to 1 with 1 M HCl. The resulting solution was extracted with 2 x 100 ml EtOAc and the combined organic layers were washed with 100 ml brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 50 mg (51%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 563.

(ii) 2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. A solution of the product from the previous step (50 mg, 0.09 mmol, 1.00 equiv.) and TFA (3 ml) in CH ₂ Cl ₂ (10 ml) was stirred for 5 hours at room temperature, then concentrated under vacuum. The crude product (50 mg) was purified by Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, Xselect CSH OBD column, 30×150 mm, 5 µm; n; mobile phase, water (0.1% FA) and ACN (43.0% ACN to 55.0% over 7 minutes); detector, UV 254/220 nm, to give 15 mg (39%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 433. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.09 (s, 1H), 8.18 (s, 1H), 7.81 (dd , J=7.0, 2.0 Hz, 1H), 7.20 (t, 7=7.9 Hz, 1H), 7.14-7.02 (m, 2H), 6.95-6, 85 (m, 2H), 6.85-6.80 (m, 1H), 6.71 (s, 1H), 4.55 (s, 2H), 3.45 (tt, J=6.3, 3.0 Hz, 1H), 1.44 (s, 6H), 0.58-0.43 (m, 2H), 0.43-0.26 (m, 2H).

Example 153: 2-([5-(3-cyclopropoxyphenyl)-1-(1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

(i) 2-([5-(3-Cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy )-2-methylpropanoic acid. Solution prom. conn. H-77 (160 mg, 0.28 mmol, 1.00 equiv.) and LiOH (70 mg, 2.92 mmol, 10.54 equiv.) in THF/MeOH/H ₂ O (5/1/1 mL ) was stirred for 3 hours at room temperature. The pH was adjusted to 5 with 1 M HCl. The resulting solution was extracted with 3×20 ml EtOAc. The combined organic layers were concentrated under reduced pressure and dried to give 140 mg (90%) of the title compound as a light yellow oil. LC-MS: (ES, mass/charge): 563.2.

(ii) 2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. A solution of the product from the previous step (140 mg, 0.25 mmol, 1.00 equiv.) and HCl/dioxane (5 ml) was stirred for 3 hours at room temperature, then concentrated in vacuo. The crude product (100 mg) was purified by Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, Xselect CSH F-Phenyl OBD column, 19×150 mm, 5 µm; n; mobile phase, water (0.1% FA) and ACN (35.0% ACN to 45.0% over 7 minutes); detector, UV 254/220 nm, to give 18.9 mg (18%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 433.05. ¹ H NMR (300 MHz, DMSO) δ 13.29 (s, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H) , 7.35 (dd, J=8.4, 7.3 Hz, 1H), 7.21 (t, J=7.9, 7.9 Hz, 1H), 6.91 (dtd, J=8 .3, 5.8, 4.8, 3.0 Hz, 3H), 6.81 (m, 1H), 6.70 (s, 1H), 4.53 (s, 2H), 3.52 ( tt, J=6.2, 6.2, 3.0, 3.0 Hz, 1H), 1.44 (s, 6H), 0.46 (m, 2H), 0.36 (m, 2H) .

Example 154 2-([5-(3-cyclopropoxyphenyl)-1-(3-methyl-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid.

(i) 2-([5-(3-Cyclopropoxyphenyl)-1-(3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3 -yl]methoxy)-2-methylpropanoic acid. Solution prom. conn. H-78 (100 mg, 0.17 mmol, 1.00 equiv.) and LiOH (40 mg, 1.67 mmol, 10.00 equiv.) in THF/MeOH/H ₂ O (5/1/1 mL ) was stirred for 3 hours at room temperature. The pH value of the solution was adjusted to 5 with 1 M HCl. The resulting solution was extracted with 3×15 ml EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give 80 mg (82%) of the title compound as a light yellow oil. LC-MS: (ES, mass/charge): 577.3.

(ii) 2-([5-(3-Cyclopropoxyphenyl)-1-(3-methyl-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. A solution of the product from the previous step (80 mg, 0.14 mmol, 1.00 equiv.) in HCl/dioxane (5 ml) was stirred for 3 hours at room temperature, then concentrated in vacuo. The crude product was purified by Prep-HPLC using the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): column, Xselect CSH OBD column, 30×150 mm, 5 µm; n; mobile phase, water (0.1% FA) and ACN (40.0% ACN to 50.0% over 7 minutes); detector, UV 254/220 nm, to give 8.2 mg (13%) of the title compound as a white solid. LC-MS: (ES, mass/charge): 447.15. ¹ H NMR (300 MHz, MeOD) δ 7.62 (dd, J=8.5, 0.8 Hz, 1H), 7.42 (dd, J=8.5, 7.2 Hz, 1H), 7.17 (t, J=7.9, 7.9 Hz, 1H), 6.99 (m, 2H), 6.80 (m, 3H), 4.65 (s, 2H), 3.25 (dt, J=5.7, 2.6, 2.6 Hz, 1H), 2.07 (s, 3H), 1.54 (s, 6H), 0.41 (m, 4H).

The following substituted pyrazolecarboxylic acids were obtained by LiOH hydrolysis of the corresponding methyl esters.

The activity of the compounds in Examples 1-269 as MCT4 inhibitors is illustrated in the following assays. Other compounds listed above that have not yet been prepared and/or tested are also predicted to have activity in such assays.

Bioactivity assays

The following are assays that can be used to evaluate the biological efficacy of the compounds of formula (I) in a manner similar to those previously described for MCT1 and MCT4, and which are known to those skilled in the art. See, for example, Murray, S.M. et al., "Monocarboxylate transporter MCT1 is a target for immunosuppression," Nature chemical biology 1, 371-376 (2005); and Ovens, M.J., et al., "AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10," The Biochemical Journal 425, 523-530, (2010).

Obtaining cells with BCECF loading.

Cells (~7x10 ⁶ ) are trypsinized (0.05% trypsin-EDTA), pelleted (300g, 5 min.) and resuspended in 1 ml Tyrode solution, pH 7.4 (119 mM NaCl, 5 mM KCl, 25 mM HEPES, pH 7.4, 2 mM CaCl ₂ , 2 mM MgCl ₂ , 6 g/l glucose). 10 µl of a 30 mM stock DMSO solution of BCECF-AM ester (Life Technologies) was added and the cells were incubated at 37° C. for 5 min. Cells are pelleted (300g, 5 min.), washed once with 1 ml Tyrode solution, pH 7.4, reprecipitated (300g, 5 min.) and resuspended in 1 ml Tyrode solution, pH 7.4.

Assay 1. Lactate transport in MCT4 repressive MDA-MB-453 breast cancer cells.

MCT4 can be stably expressed in MDA-MB-453 breast cancer cells that do not express native MCT1 or MCT4. MCT4 activity can be assessed by monitoring the change in intracellular pH that accompanies lactate/proton symport using the pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), in a manner similar to that described previously for MCT1 and MCT4. The following is an exemplary assay procedure for MCT4 activity of compounds of formula (I).

Assay 2. MCT4 mediated lactate transport in NCI-H358 lung adenocarcinoma cells.

Lung adenocarcinoma NCI-H358 cells can be used to measure MCT4 activity in cells with high native MCT4 levels and low MCT1 levels and are known to those skilled in the art. Cell production with BCECF loading and lactate transport activity can be determined as described for assay 1.

Analysis 3. MCT4 mediated lactate transport in MDA-MB-231 breast cancer cells.

MDA-MB-231 breast cancer cells can be used to measure MCT4 activity in cells with high native MCT4 levels and low MCT1 levels and are known to those skilled in the art. MCT4 activity can be assessed by monitoring the change in intracellular pH that accompanies lactate/proton symport using the pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), in a manner similar to that described previously for MCT1 and MCT4. The following is an exemplary assay procedure for MCT4 activity of compounds of formula (I).

Analysis 4. MCT1-mediated lactate transport in BT20 breast cancer cells.

MCT1 activity can be measured using breast cancer BT-20 cells that express high native levels of MCT1 but do not express MCT4 and are known to those skilled in the art. Preparation of cells loaded with BCECF is described for assay 1. The lactate transport assay is as described for assay 1, except for the addition of 10 mM L-lactate (rather than 50 mM).

The results of the above analyzes are presented below in tables 26 and 27, in which "ND" means no data. As can be seen, most of the compounds disclosed herein are more selective for MCT4 than MCT1.

Metabolic stability assays

The following are assays that can be used to evaluate the metabolic stability of compounds of formula (I) in human, rat or mouse microsomes. The analyzes follow the generally accepted procedure outlined below.

1. Stock solution: 200 µl 200 mM phosphate buffer, 106 µl ultrapure water, 40 µl 50 mM MgCl ₂ and 10 µl 20 mg/ml liver microsomes (human, rat or mouse).

2. Two separate experiments were performed as follows, a) With NADPH: 10 µl of 20 mg/ml liver microsomes and 40 µl of 10 mM NADPH were added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg/ml and 1 mM, respectively. b) Without NADPH: 10 µl of 20 mg/ml liver microsomes and 40 µl of ultrapure H ₂ O were added to the incubations. The final concentration of microsomes was 0.5 mg/ml.

3. The reaction was started by adding 4 μl of 200 μM solutions of the control compound or test compound. Verapamil was used as a positive control in this study. The final concentration of test compound or control compound was 2 μM.

4. Aliquots of 50 µl were taken from the reaction solution at 0, 15, 30, 45 and 60 minutes. The reaction was stopped by adding 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol and 2 μM ketoprofen). Samples were centrifuged at 3220 g for 40 minutes. An aliquot of 90 μl of the supernatant was mixed with 90 μl of ultrapure H ₂ O and then used for LC-MS/MS analysis.

5. Data analysis. All calculations were performed using Microsoft Excel. Peak areas were determined from the obtained ion chromatograms. The value of the slope angle, k, was determined by linear regression of the natural logarithm of the remaining percentage of the original drug against the incubation time curve. The in vitro half-life (in vitro t _1/2 ) was determined based on the value of the slope angle: in vitro t _1/2 = -(0.693)/k.

The results are presented below in table 28, where "ND" means no data.

Pharmacokinetic assays in mice and rats

The following are assays that can be used to evaluate the pharmacokinetic properties of formula (I) in mice or rats. The analyzes follow the generally accepted procedure outlined below.

1. Compositions. For IV, DMSO/PEG400/30%HP-β-CD (10:20:70); For PO (oral gavage tube), DMSO/PEG400 (10:90). The formulations were received fresh on the day of dosing or prior to dosing. Storage at room temperature.

2. Species under study. For mice: CD1 males, approximately 6-8 weeks of age, approximately 20-30 g. For rats: Male Sprague-Dawley strains, approximately 6-8 weeks of age, approximately 200-300 g.

3. Dose level: for IV, 3 mg/kg. for RO, 10 mg/kg.

4. Number of animals: 3 per analysis.

5. Moments of time PK. For IV (blood plasma): 5 min, 15 min, 1, 2, 4, 6, 8, 24 hours post-dose. For PO (blood plasma): 15 min, 30 min, 1, 2, 4, 6, 8, 24 hours post-dose.

6. Collection and processing of blood samples. Blood was collected (~0.2 ml at time) from the jugular vein. Blood from each sample was transferred into plastic micro centrifuge tubes containing the anticoagulant EDTA-K ₂ . Blood samples were centrifuged at 2000 g for 5 minutes at 4°C to obtain blood plasma.

7. Sample analysis. Blood plasma samples were analyzed using the LC/MS/MS method and pharmacokinetic parameters (half-life: t _1/2 ; oral bioavailability: F; volume of distribution: Vss).

The results are presented below in table 29, where "ND" means no data.

Rat Adjuvant-Induced Arthritis Model

The following assays are used to evaluate the anti-inflammatory properties of formula (I) in the rat. The analyzes follow the generally accepted procedure outlined below.

1. Composition: 0.5% methylcellulose in saline. The formulation was received fresh on the day of dosing.

2. Species under study. Rat SD, approximately 6-8 weeks of age, approximately 200 g.

3. Arthritis induction procedure. Freund's complete adjuvant (CFA; 50 μl/rat, M. tuberculosis at 4 mg/ml) was administered by subplant injection in the left paw.

4. Dose administration: PO (oral by gastric tube), 3 days after CFA injection.

5. Body weight. The body weights of all animals were recorded during the study on day 1 and day 3.

6. Weight difference study (DWB). The distribution of body weight in rats between the injected CFA and the opposite paw was measured using a weight-balance instrument. Animals were tested to record the weight load applied by the hind legs by means of a stabilograph inserted into the floor. The average weight load (in g) between the CFA-injected paw and the opposite paw was determined for 10 seconds. Measurements were taken three times including pre-dose baseline, 1 hour and 4 hours post-dose on day 3.

7. Study of mechanical allodynia (MA). The mechanical allodynia of the left hind paw will be measured at the time of the study by determining the withdrawal threshold from von Frey filaments. The thread was applied perpendicular to the flat surface of the paw with increasing force. The paw withdrawal threshold was calculated by taking the average of 2-3 repeated stimuli (in g) that induced the paw withdrawal reflex. Measurements were taken three times, including pre-dose baseline, 1 hour and 4 hours post-dose on day 3.

8. The minimum effective dose was determined by comparing the compounds of formula (I) with dexamethasone, which is a positive control.

All references, patents or patent applications, US or foreign, cited in this application are hereby incorporated by reference as if they were written in this document in their entirety. In the event of any inconsistency, the material disclosed in this document takes precedence.

From the foregoing description, a person skilled in the art can readily ascertain the main features of the present invention and, without departing from its spirit and scope, may make various changes and modifications to the present invention to adapt it to various applications and conditions.

Claims (44)

1. Compound of structural formula VII

or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond and methylene; W represents

; Y is selected from

and

; R ^2c is selected from H, C ₁ -C ₄ alkoxy and C ₁ -C ₄ cycloalkoxy; R ^2d is absent or selected from C ₁ -C ₄ alkoxy; R ^2e is C ₁ -C ₄ alkyl; n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl); R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and R ⁶ is selected from H and C ₁ -C ₄ alkyl. 2. A compound according to claim 1 wherein n is 1 to form azetidin-1-yl. 3. A compound according to claim 2, wherein L is a bond. 4. The compound according to claim 1, where the compound is characterized by the structural formula VIII

or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond and methylene; Y is selected from

and

; n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl); R ^2c is selected from H, C ₁ -C ₄ alkoxy and C ₁ -C ₄ cycloalkoxy; R ^2d is absent or selected from C ₁ -C ₄ alkoxy; R ^2e is C ₁ -C ₄ alkyl; R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and R ⁶ is selected from H and C ₁ -C ₄ alkyl. 5. The compound according to claim. 1, where the compound is characterized by the structural formula XI

or a pharmaceutically acceptable salt thereof, wherein W represents

; m is 1, 2 or 3 (to form cyclopropyl, cyclobutyl or cyclopentyl); L is selected from bond and methylene; Z represents

; n is 1 or 2 (to form azetidin-1-yl or pyrrolidin-1-yl); R ⁴ and R ⁵ are independently selected from C ₁ -C ₃ alkyl; and R ⁶ is selected from H and C ₁ -C ₄ alkyl. 6. A compound of structural formula VII according to claim 1, selected from

or a pharmaceutically acceptable salt thereof. 7. The use of a compound according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof in the treatment of an MCT4 monocarboxylate transporter mediated disorder in a subject in need thereof. 8. Use according to claim 7 wherein the MCT4 monocarboxylate transporter-mediated disorder is a proliferative disorder. 9. Use according to claim 8, wherein the proliferative disorder is cancer. 10. The use of claim 9 wherein the cancer is selected from adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, stomach cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, colon cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal cord tumor, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer thyroid cancer, throat cancer, genitourinary cancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms tumor. 11. Use according to claim 7 wherein the MCT4 monocarboxylate transporter-mediated disorder is an inflammatory disorder. 12. Use according to claim 11 wherein the inflammatory disorder is selected from Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma).