The present invention relates to compounds that inhibit activity of the histone lysine methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, such as hematologic and solid tumors.

EZH2 is encoded by the EZH2 gene, and is the catalytic component within polycomb repressive complex 2 (PRC2) that is responsible for the methylation of lysine 27 on histone 3 (H3K.27) on chromatin. EZH2 overexpression is thought to promote cancer as a result of increases in histone methylation which silences the expression of tumor suppressor genes. The catalytic activity of EZH2 is mediated by a 130 amino acid Su( var)3-9, enhancer of Zeste and trithorax (SET) domain, which provides the binding pockets for S-adenosylmethionine (SAM) co factor and the lysine substrate residue. The core PRC2 complex is comprised of EZH2 and proteins EED (Embryonic Ectoderm Development), SUZ12 (Suppressor of Zeste 12 homolog) and RbAp46/48 (also known as RBBP7/4), and can also include other proteins such as JARID2, AEBP2, and

Polycomblike (PCL) 1 /2/3.

In addition to overexpression of EZH2, increased H3K27 methylation can also arise due to mutations which increase the catalytic efficiency of EZH2, such as Y641N, A677G, and A678V. In addition, it is also reported that levels of H3K27 methylation can be modulated in solid tumors through various signaling pathways, such as those involving VEGFR2 and PI3K/AKT.

The SWI/SNF and PRC2 complexes play antagonistic roles in the activation and repression of transcription, respectively. Tumors that lack or are defective in SWI/SNF protein SNF5 (also known as SMARCB1/INI1) can demonstrate aberrant methylation and repression by PRC2 and are growth-inhibited following treatment with EZH2 small molecule inhibitors. In addition, tumors that lack or are defective in SWI/S F protein ARID 1 A (also known as BAF250), combined with constitutively activating mutations in components of the PI3K pathway such as PI 3CA, are also growth-inhibited following treatment with EZH2 small molecule inhibitors. In addition, tumors that lack or are defective in both SMARCA2 (also known as BRM) and SMARCA4 (also known as BRG l ) are also growth-inhibited following treatment with EZH2 small molecule inhibitors.

H3K4 methyltransferase (also known as MLL or CO PASS) complexes cooperate with the SWI/'S F complex in antagonizing the repressive effects of PRC2 (reviewed in Van der Meulen, J. et al. (2014) Epigenetics 9:658-68, Xu, B. et al. (2015) Exp. Hematol. 43:698-712) Tumors that lack or are defective in H3K.4 methyltransferase complex components , including but not limited to MLL2 (data shown herein for combination treatment with an EZH2 inhibitor plus Standard of Care chemotherapy in patient-derived xenograft models of gastric cancer), MLL3 (data shown herein for combination treatment with an EZH2 inhibitor plus Standard of Care chemotherapy in patient-derived xenograft models of lung cancer), Lysine-specific demethylase 6A, also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX, also known as KDM6A [Ezponda, T. et al. (2014) Blood 124:61 1 j), alone or in combination with the lack or defect in components of the SWI/S F complex described above, including but not limited to ARID 1 A (data shown herein for combination treatment with an EZH2 inhibitor plus Standard of Care chemotherapy in patient-derived xenograft models of gastric cancer), are growth-inhibited following treatment with EZH2 small molecule inhibitors as a single-agent or in combination with Standard of Care (SOC) chemotherapeutic agents. Lymphomas with germinal center B-cell origins are growth-inhibited with perturbations in EZH2 (Beguelin et al. (2013) Cancer Cell 23:677-92; Velichutina, I. et al. (2010) Blood 1 1 6:5247-5255) and also have a high frequency of mutations in MLL2, CREBBP, EP300, ARID 1 A and SMARCA4 (Lunning, M.A. and Green, M.R. (2015) Blood Cancer Journal 5, e361 ; Carbone, A. et al. (2014) Ann.

Hematol. 93: 1263- 1277).

Some EZH2 inhibitors are already known in the literature. See for example, WO2012/ 142504, WO2012/1425 13, WO2013/120104, WO2013/ 173441 ,

WO2013/075083, WO2014/ 177982, WO2014/097041 , and WO2016/066697.

There remains a need to provide alternative EZH2 inhibitors for treatment of cancer. Accordingly, the present invention provides certain inhibitors of EZH2 which may be useful for treating cancer.

The present invention provides a compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-;

Y' is -NR4R5, CH(CH3)-cyclohex-4-yl-dimethylamino, CH(CH3)-cyclohex-4-yl-N-methyl-N-methoxyethylamino, or -CH(CH3)-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, N-triazolyl, N-pyrrolidinyl, mo holinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl;

R4 is piperidin-4-yl or cyclohex-4-yl substituted with dimethylamino, N -methyl -N-methoxyethylamino, N-methyl-N-cyclopropylamino, or azetidin- 1 -yl wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-;

Y' is -NR4R5, -CH(CH3)-cyclohexyl-4-yl-N-methyl-N-methoxyethyl, or - CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, pyrazolyl, methylpyrazolyl, triazolyl, pyrrolidinyl,

tetrahydrofuranyloxy, or mo holinyl;

R4 is cyclohex-4-yl substituted with N-methyl-N-methoxyethylamino, N-methyl- N-cyclopropylamino, or azetidin- 1 -yl wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or pyrazolyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-;

Y' is -NR4R5, CH(CH3)-cyclohex-4-yl-dimethylamino, CH(CH3)-cyclohex-4-yl-N-methyl-N-methoxyethylamino, or -CH(CH3)-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, N-triazolyl, -pyrrolidinyl, mo holinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl;

R4 is cyclohex-4-yl substituted with dimethylamino, N -methyl -N-methoxyethylamino, N-methyl-N-cyclopropylamino, or azetidin- 1 -yl wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-;

Y' is -NR4R5, CH(CH3)-cyclohex-4-yl-N-methyl-N-methoxyethylamino, or -CH(CH )-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy,

cyclopropylmethoxy, N-triazolyl, N-pyrrolidinyl, morpholinyl, tetrahydro furan-3 -yloxy, or N-pyrazolyl optionally substituted with methyl;

R4 is cyclohex-4-yl substituted with N-methyl-N-methoxyethylamino, N-methyl-N-cyclopropylamino, or azetidin- 1 -yl wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-;

Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydro furan-3 -yloxy, or N-pyrazolyl optionally substituted with methyl; and

R6 is methyl; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-;

Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydro furan-3-y oxy, or N-pyrazolyl optionally substituted with methyl; and

R6 is methyl; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-CH2-;

Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydrofuran-3-yloxy, or N-pyrazoly optionally substituted with methyl; and

R6 is methyl; or

a pharmaceutically acceptable salt thereof.

Th resent invention also provides a compound of the formula:

wherein:

Y' is -NR4R5;

R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl; and

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-;

Y' is -NR4R5;

R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2-CH2-;

Y' is -NR4R5;

R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl; or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

Y' is-CH(CH3)-cyclohex-4-yl -azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy,

cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof; wherein the carbon attached at the 2 position of the 6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one is in the (R) configuration.

The present invention also provides a compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-;

Y' is-CH [CH3]-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof; wherein the carbon attached at the 2 position of the 6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one is in the (R) configuration and the cyclohexane ring is in the trans configuration.

The present invention also provides a compound of the formula:

wherein:

Y' is -NR4R5;

R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or N-pyrazolyl optionally substituted with methyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or

a pharmaceutically acceptable salt thereof; wherein the cyclohexane ring is in the trans configuration.

The present invention also provides a compound of the formula:

O

"

wherein:

X is -CH2- or -CH2-CH2-; and

Y is CHCH3, N(CH3), or N(CH2CH3); or

a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-; and

Y is CHCH3, N(CH3), or N(CH2CH3); and

R7 is hydrogen, methoxy, ethoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl; or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

- I O-

wherein:

X is -CH2- or -CH2-CH2-;

Y is CHCH3, N(CH3), or N(CH2CH3); and

R7 is hydrogen, methoxy, ethoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholinyl, N-triazolyl, N-pyrrolidinyl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl; or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of the formula:

O

wherein:

X is -CH2- or -CH2-CH2-; and

Y is CHCH3, N(CH3), or N(CH2CH3); or

a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is

O

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is o

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is

O

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is o

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is o

nnaceutically acceptable salt thereof.

The present invention provides a compound which is

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which o

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is o

rmaceutically acceptable salt thereof.

The present invention provides a compound which is

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is

or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is o

or a pharmaceutically acceptable salt thereof.

The present invention provides a method of treating cancer in a patient, wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SNF complex (for instance, SNF5), MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastric cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer comprising administering to the patient an effective amount of a compound or salt thereof of the present invention. Preferably the cancer is diffuse large B-cell lymphoma or follicular lymphoma.

Preferably the cancer is diffuse large B-cell lymphoma. Preferably the cancer is gastric cancer. Preferably the cancer is ovarian cancer. Preferably the cancer is multiple myeloma. Preferably the cancer is lung cancer. Preferably the cancer is colorectal cancer. Preferably the cancer is a solid or hematological tumor that bears wild type (WT) EZH2 as well as a solid or hematological tumor that bears mutant EZH2.

Preferably the cancer is a solid or hematological tumor that bears WT EZH2. Preferably the cancer is a solid or hematological tumor that bears mutant EZH2.

The present invention also provides for a method of treating ovarian cancer in a patient comprising administering to the patient a compound or salt thereof of the present invention in combination with carboplatin and paclitaxel

The present invention also provides for a method of treating gastric cancer in a patient comprising administering to the patient a compound or salt thereof of the present invention in combination with oxaliplatin and paclitaxel.

The present invention also provides for a method of treating lung cancer in a patient comprising administering to the patient a compound or salt thereof of the present invention in combination with gemcitabine and cisplatin.

The present invention also provides for a method of treating colorectal cancer in a patient comprising administering to the patient a compound or salt thereof of the present invention in combination with irinotecan and oxaliplatin.

The present invention also provides a pharmaceutical composition comprising a compound or salt thereof of the present invention and one or more pharmaceutically acceptable excipients, carriers, or diluents.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention and carboplatin and paclitaxel for the treatment of ovarian cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients, and carboplatin with one or more pharmaceutically acceptable carriers, diluents, or excipients and paclitaxel with one or more pharmaceutically acceptable carriers, diluents, or excipients for the treatment of ovarian cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention and oxaliplatin and paclitaxel for the treatment of gastric cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients, and oxaliplatin with one or more pharmaceutically acceptable carriers, diluents, or excipients and paclitaxel with one or more pharmaceutically acceptable carriers, diluents, or excipients for the treatment of gastric cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention and gemcitabine and cisplatin for the treatment of lung cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients, and gemcitabine with one or more pharmaceutically acceptable carriers, diluents, or excipients and cisplatin with one or more pharmaceutically acceptable carriers, diluents, or excipients for the treatment of lung cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention and irinotecan and oxaliplatin for the treatment of colorectal cancer.

According to another aspect of the present invention, there is presented a kit comprising a compound or salt thereof of the present invention with one or more

pharmaceutically acceptable carriers, diluents, or excipients, and irinotecan with one or more pharmaceutically acceptable carriers, diluents, or excipients and oxaliplatin with one or more pharmaceutically acceptable carriers, diluents, or excipients for the treatment of colorectal cancer.

This invention also provides a compound or salt thereof of the present invention for use in therapy. Additionally, this invention provides a compound or salt thereof of the present invention for use in the treatment of cancer wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/S F complex (for instance, SNF5), MLL complexes, and constitutively active P13 pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer. Preferably the cancer is diffuse large B-cell lymphoma or follicular lymphoma. Preferably the cancer is diffuse large B-cell lymphoma. Preferably the cancer is gastric cancer. Preferably the cancer is ovarian cancer. Preferably the cancer is multiple myeloma. Preferably the cancer is lung cancer. Preferably the cancer is colorectal cancer. Preferably the cancer is a solid or

hematological tumor that bears wild type (WT) EZH2 as well as a solid or hematological tumor that bears mutant EZH2. Preferably the cancer is a solid or hematological tumor that bears WT EZH2. Preferably the cancer is a solid or hematological tumor that bears mutant EZH2.

Furthermore, this invention provides the use of a compound or a salt thereof of the present invention in the manufacture of a medicament for treating cancer wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SNF complex (for instance, SNF5), MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer. Preferably the cancer is diffuse large B-cell lymphoma or follicular lymphoma. Preferably the cancer is diffuse large B-cell lymphoma. Preferably the cancer is gastric cancer. Preferably the cancer is ovarian cancer. Preferably the cancer is multiple myeloma. Preferably the cancer is lung cancer. Preferably the cancer is colorectal cancer. Preferably the cancer is a solid or hematological tumor that bears wild type ( WT) EZH2 as well as a solid or

hematological tumor that bears mutant EZH2. Preferably the cancer is a solid or hematological tumor that bears WT EZH2. Preferably the cancer is a solid or hematological tumor that bears mutant EZH2.

According to another aspect of the present invention, there is presented a combination comprising a compound or salt thereof of the present invention and carboplatin and paclitaxel for simultaneous, separate, or sequential use in the treatment of ovarian cancer.

According to another aspect of the present invention, there is presented a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with carboplatin and paclitaxel in the treatment of ovarian cancer.

According to another aspect of the present invention, there is presented carboplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and paclitaxel in the treatment of ovarian cancer.

According to another aspect of the present invention, there is presented paclitaxel for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and carboplatin in the treatment of ovarian cancer.

The present invention also provides for use of a compound or salt thereof of the present invention in the manufacture of a medicament for the treatment of ovarian cancer wherein the compound or salt thereof of the present invention is to be administered in simultaneous, separate or sequential combination with carboplatin and paclitaxel.

The present invention also provides for use of carboplatin in the manufacture of a medicament for the treatment of ovarian cancer wherein the carboplatin is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and paclitaxel.

The present invention also provides for use of paclitaxel in the manufacture of a medicament for the treatment of ovarian cancer wherein the paclitaxel is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and carboplatin.

According to another aspect of the present invention, there is presented a combination comprising a compound or salt thereof of the present invention and oxaliplatin and paclitaxel for simultaneous, separate, or sequential use in the treatment of gastric cancer.

According to another aspect of the present invention, there is presented a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with oxaliplatin and paclitaxel in the treatment of gastric cancer.

According to another aspect of the present invention, there is presented oxaliplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and paclitaxel in the treatment of gastric cancer.

According to another aspect of the present invention, there is presented paclitaxel for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and oxaliplatin in the treatment of gastric cancer.

The present invention also provides for use of a compound or salt thereof of the present invention in the manufacture of a medicament for the treatment of gastric cancer wherein the compound or salt thereof of the present invention is to be administered in simultaneous, separate or sequential combination with oxaliplatin and paclitaxel.

The present invention also provides for use of oxaliplatin in the manufacture of a medicament for the treatment of gastric cancer wherein the oxaliplatin is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and paclitaxel.

The present invention also provides for use of paclitaxel in the manufacture of a medicament for the treatment of gastric cancer wherein the paclitaxel is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and oxaliplatin.

According to another aspect of the present invention, there is presented a combination comprising a compound or salt thereof of the present invention and gemcitabine and cisplatin for simultaneous, separate, or sequential use in the treatment of lung cancer.

According to another aspect of the present invention, there is presented a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with gemcitabine and cisplatin in the treatment of lung cancer.

According to another aspect of the present invention, there is presented gemcitabine for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and cisplatin in the treatment o f lung cancer.

According to another aspect of the present invention, there is presented cisplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and gemcitabine in the treatment of lung cancer.

The present invention also provides for use of a compound or salt thereof of the present invention in the manufacture of a medicament for the treatment of lung cancer wherein the compound or salt thereof of the present invention is to be administered in simultaneous, separate or sequential combination with gemcitabine and cisplatin.

The present invention also provides for use of gemcitabine in the manufacture of a medicament for the treatment of lung cancer wherein the gemcitabine is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and cisplatin.

The present invention also provides for use of cisplatin in the manufacture of a medicament for the treatment of lung cancer wherein the cisplatin is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and gemcitabine.

According to another aspect of the present invention, there is presented a combination comprising a compound or salt thereof of the present invention and irinotecan and oxaliplatin for simultaneous, separate, or sequential use in the treatment of colorectal cancer.

According to another aspect of the present invention, there is presented a compound or salt thereof of the present invention for use in simultaneous, separate or sequential combination with irinotecan and oxaliplatin in the treatment of colorectal cancer.

According to another aspect of the present invention, there is presented irinotecan for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and oxaliplatin in the treatment of colorectal cancer.

According to another aspect of the present invention, there is presented oxaliplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and irinotecan in the treatment of colorectal cancer.

The present invention also provides for use of a compound or salt thereof of the present invention in the manufacture of a medicament for the treatment of colorectal

cancer wherein the compound or salt thereof of the present invention is to be administered in simultaneous, separate or sequential combination with innotecan and oxaliplatin.

The present invention also provides for use of innotecan in the manufacture of a medicament for the treatment of colorectal cancer wherein the irinotecan is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and oxaliplatin.

The present invention also provides for use of oxaliplatin in the manufacture of a medicament for the treatment of colorectal cancer wherein the oxaliplatin is to be administered in simultaneous, separate, or sequential combination with a compound or salt thereof of the present invention and irinotecan.

The following paragraphs describe preferred classes of the present invention: a) X is -CH2- b) X is -CH2-CH2-;

c) Y' is -CH(CH3)-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, cyclopropyloxy, or tetrahydrofuran-3- yloxy;

d) Y' is NR4R5;

e) R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxy or methoxyethoxy;

f) R5 is ethyl;

g) R6 is methyl;

h) X is -CH2-, Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is substituted with methoxy, and R6 is methyl;

i) X is -CH2-, Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is substituted with cyclopropyloxy, and R6 is methyl;

j) X is -CH2-, Y' is -CH(CH3)-cyclohex-4-yl -azetidin- 1-yl wherein the azetidin- 1 -yl is substituted with tetrahydrofuran-3-yloxy, and R6 is methyl; k) X is -CH2-, Y' is NR4R5, R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the

azetidin- 1 -yl is substituted with methoxy, R5 is ethyl, and R6 is methyl;

1) X is -CH2-CH2-, Y' is NR4R5, R4 is cyclohex-4-yl-azetidin- 1 -yl, wherein the azetidin- 1 -yl is substituted with methoxyethoxy, R5 is ethyl, and R6 is methyl; and

m) X is CH2-CH2-, Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin-1 -yl is substituted with methoxy, and R6 is methyl.

It will be understood by one of ordinary skill in the art that the term "trans-" is as depicted below wherein substituents at the 1 ,4 positions around the cyclohexyl moiety are trans- relative to one another:

wherein R is selected from among dimethylamino, N -methyl -N -methoxyethylamino, N-cyclopropyl-N-methylamino, or azetidin- 1 -yl, optionally substituted with methoxy, ethoxy, propoxy, methylmethoxy, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, morpholiny , N -triazolyl, pyrrolidin-4-yl, tetrahydrofuran-3-yloxy, or N-pyrazolyl optionally substituted with methyl and X and Y are as previously defined.

It will be understood by the skilled reader that a compound of the present invention is capable of forming salts. The compound of the present invention is a base, and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable salts. Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the art. See, for example, P. Stahl, et al, HANDBOOK OF PHARMACEUTICAL SALTS:

PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); S.M. Berge, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No. 1 , January 1977.

A compound or salt thereof of the present invention may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps described may be combined in different ways to prepare compounds or salts of the present invention. The products of the synthetic steps can be recovered by conventional methods well known in the art,

including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

Some intermediates or compounds of the present invention may have one or more chiral centers. The present invention contemplates all individual enantiomers or diastereomers, as well as mixtures of the enantiomers and diastereomers of said compounds including racemates. It is preferred that compounds of the present invention containing at least one chiral center exist as single enantiomers or diastereomers. The single enantiomers or diastereomers may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, the single enantiomers or diastereomers may be isolated from mixtures by standard chiral chromatographic or crystallization techniques. The skilled artisan will appreciate that in some circumstances the elution order of enantiomers or diastereomers may be different due to different chromatographic columns and mobile phases.

Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, or diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the present invention by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981 , and E.L. Eliel and S.I I. Wilen," Stereochemistry of Organic

Compounds", Wiley-Interscience, 1994). Additionally, the intermediates described in the following schemes contain a number of nitrogen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example "Greene 's Protective Groups in Organic Synthesis", Fourth Edition, by Peter CM. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

Certain abbreviations are defined as follows: "AcOH" refers to acetic acid or glacial acetic acid; "ACN" refers to acetonitrile; "Ado et" refers to S-adenosyl-L-

methionine; "A EBP" refers to adipocyte-enhancer binding protein; "AUG" refers to Area Under the Curve; "BOC" refers to tert-b utox ycarbony 1 ; "bid" refers to twice a day dosing; "bm" refers to broad multiplet; "Bn" refers to benzyl; "BSA" refers to Bovine Serum Albumin; "c" refers to concentration in grams per milliliter; "CAT. #" Refers to catalog number; "CD I" refers to carbonyldiimidazole; "C02" refers to carbon dioxide; "CV" refers to column volume; "Ci" refers to Curie; "CPM" refers to counts per million; "cPr" refers to cyclopropyl; "DCE" refers to 1 ,2-dichloroethane; "DCM" refers to methylene chloride or dichloromethane; "DIBAL-H" refers to diisobutyl aluminum hydride; "DIPEA" refers to diisopropyl ethyl amine; "dm" refers to decimeters or 10 centimeters; "DMA" refers to dimethylacetamide; "DMEA" refers to N, N-dimethylethylamine; "DMF" refers to dimethyl formamide or N , -di methyl formamide; "DMSO" refers to dimethyl sulfoxide; "DNase" refers to deoxyribonuclease; "DTT" refers to dithiothreitol; "EED" refers to embryonic ectoderm development; "Et20" refers to diethyl ether; "EtOAc" refers to ethyl acetate; "ES/MS" refers to electrospray mass spectrometry; "EtOH" refers to ethanol or ethyl alcohol; "Ex" refers to example;

"GAPDH" refers to glyceraldehyde 3 -phosphate dehydrogenase; "hr" refers to hour or hours; "HEC" refers to hydroxy ethyl cellulose; "HOAt" refers to

hydroxyazabenzotriazole; "HOBt" refers to hydroxybenzotriazole; "HSQC" refers to Heteronuclear Single Quantum Coherence; "IP Am" refers to isopropylamine, propan-2-amine, or 2-aminopropane; "iPr" refers to isopropyl or 1 -methyl ethyl; "IrMeO(COD)2" refers to ( 1 ,5-cyclooctadiene)(methoxy)iridium(I) dimer or bis( 1 ,5-cyclooctadiene)di-n-methoxydiiridium(I); "kPa" refers to kilopascal or kilopascals; "K.HMDS" refers to potassium bis(trimethylsilyl)amide; "KOtBu" refers to potassium-tert-butoxide or potassium-t-butoxide; "LAH" refers to lithium aluminum hydride; "LiBH4" refers to lithium borohydride; "LC" refers to liquid chromatography; "Li HMDS" refers to lithium bis(trimethylsilyl)amide; "LOF" refers to Loss of Function; "3H-SAM" refers to adenosyl-L-methionine, S[ methyl- H]; "IC5o" refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent; "Me" refers to methyl; "MgS04" refers to magnesium sulfate; "mpk" refers to milligrams per kilogram; "min" refers to minute or minutes; "NaH" refers to sodium hydride; "NBS" refers to N-bromosuccinimide; "NH3" refers to ammonia; "nm" refers to nanometer or nanometers; "MeOH" refers to methanol or methyl alcohol; "MsOH" refers to methanesulfonic acid;

"MTBE" refers to methyl fert-butyl ether; "mut" refers to mutant; "OAc" refers to acetate; "PBS" refers to phosphate buffered saline; "PGR" refers to polymerase chain reaction; "PDX" refers to patient-derived xenograft; "PRC2" refers to Polycomb

Repressive Complex 2"; "Prep" refers to preparation; "psi" refers to pounds per square inch; "PTSA" refers to para- toluene sulfonic acid; "quantitative yield" refers to essentially greater than 99% yield; "RBBP4" refers to retinoblastoma binding protein 4; "RNase" refers to ribonuclease; "rpm" refers to revolutions per minute; "RT" refers to room temperature; "R " refers to retention time in minutes; "RuPhos-G3-Palladacycle" refers to (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , -biphenyl)]palladium(II) methanesulfonate; "SCX" refers to selective cation exchange; "SFC" refers to supercritical fluid chromatography; "SPA" refers to scintillation proximity assay; "NaHCC " refers to sodium bicarbonate; "NaiSO.4" refers to sodium sulfate; "SoC" refers to Standard of Care; "THF" refers to tetrahydrofuran, "TEA" refers to triethylamine; "Tris" refers to tris(hydroxymethyl)-aminomethane; "WT" refers to wild type; "XPhos Pd Gen 2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-I . I '-biphenyl)-[2-(2'-amino- 1. 1 '-biphen-yl)]-palladium(II); "A" refers to angstrom or angstroms; "λ" refers to wavelength; and "[a]D20" refers to the optical rotation of a compound that rotates plane-polarized light using the D-line of a sodium lamp

(wavelength 589.3 nm) in a polarimeter, with an observed polarimetry measurement a, in a suitable solvent such as MeOH, measured at 20 °C, at a defined concentration c, a volume of 2 mL, and a path length of 1 dm.

In the schemes below, all substituents, unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The following schemes, preparations, examples, and assays further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

Preparations and Examples

The following Preparations and Examples further illustrate the invention and represent typical synthesis of the compounds of the invention. The reagents and starting materials are readily available or may be readily synthesized by one of ordinary skill in the art. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

The R- or S- configuration of the compounds of the invention may be determined by standard techniques such as X-ray analysis. 1 H NMR, chiral HPLC, and correlation with chiral-HPLC retention time may be used to further elucidate stereoisomerism if one center is known.

LC-ES/MS is performed on an Agilent HP 1 100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to the HP 1 100 HPLC. LC-MS conditions (low pH): column: Phenomenex

GEMINI® NX C-18 2.1 50 mm 3.0 μΐη; gradient: 5- 100% B in 3 min, then 100% B for 0.75 min column temperature: 50 °C +/- 10 °C; flow rate: 1 .2 mL/min; Solvent A:

deionized water with 0.1 % HCOOH; Solvent B: ACN with 0.1 % formic acid;

wavelength 214 nm. Alternate LC-MS conditions (high pH): column: WATERS™ XTERRA® MS C- 1 8 columns 2.1 x 50 mm, 3.5 μΐη; gradient: 5% of solvent A for 0.25 min, gradient from 5% to 100% of solvent B in 3 min and 100% of solvent B for 0.5 min or 10% to 100% of solvent B in 3 min and at 100% of solvent B for 0.75 min; column temperature: 50 °C +/- 10 °C; flow rate: 1 .2 mL/min; Solvent A: 10 mM NH4HCO3 pH 9; Solvent B: ACN ; wavelength: 214 nm.

Preparative reversed phase chromatography is performed on an Agilent 1200 LC- ES/MS equipped with a Mass Selective Detector mass spectrometer and a Leap autosampler/fraction collector. High pH methods are run on a 75 X 30 mm Phenomenex GEMINI®-NX, 5 μι particle size column with a 10 X 20 mm guard. Flow rate of 85 mL/min. Eluent is 10 mM ammonium bicarbonate (pH 10) in ACN.

NMR spectra are performed on a Bruker AVI 11 HD 400 MHz NMR Spectrometer, obtained as CDCI3 or (CD. 2SO solutions reported in ppm, using residual solvent [CDCI3, 7.26 ppm; (CD^SO, 2.50 ppm] as a reference standard. When peak multiplicities are reported, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants (J), when reported, are reported in hertz (Hz).

Scheme 1

Scheme 1 illustrates the formation of a substituted 1 ,4-dioxaspiro[4,5]decane (compound 5) starting from a protected 4-oxocyclohexanecarboxylate (compound 1 ). The protected 4-oxocyclohexanecarboxylate may be treated with p-toluenesulfonic acid, tri ethyl orthoformate and ethylene glycol in a solvent such as EtOH to give the protected l ,4-dioxaspiro[4,5]decane-8-carboxylic ester which may then be deprotected by procedures well known in the art, such as by using an aqueous base, to give 1 ,4-dioxaspiro[4,5]decane-8-carboxylic acid over 2 steps (compound 2, Scheme 1 , Step A). The Weinreb amide (compound 3) may be prepared from the acid product of Step A with the addition of a coupling reagent such as G DI or HOBt in small portions followed by the addition of N-methoxymethanamine hydrochloride in small portions (Scheme 1 , Step B). The Weinreb amide (compound 3) may be converted to the ketone (compound 4) using an organometallic reagent such as a Grignard reagent or an organolithium reagent (Scheme 1, Step C). More specifically, methyl magnesium bromide may be added in an appropriate solvent such as Et20 and/or THF to give the methyl ketone (compound 4). The methyl ketone (compound 4) may be converted to the vinyl phosphonate (compound 5) with drop wise addition of a non-nucleophilic base such as Li HMDS in a solvent such as THF with the addition of diphenyl phosphorochloridate (Scheme 1, Step D).

call 2

PG = protect ng group

Scheme 3

R2 = OCH3, OCH2CH3, O-cPr, O-iPr, OCH2-cPr, CH-OCH-,

( CEL^OCHj, N-pyrazolyl, N-(substituted pyrazolyl), N-triazolyl, tetrahydrofuran-3-yl, morpholinyl, N-pyrrolidinyl

Schemes 2 and 3 illustrate the syntheses of substituted azetidines. - Protected vinyloxyazetidine (compound 7a, R1 = allyl) may be prepared by alkylating the appropriately substituted 3-hydroxyazetidine (compound 6) with an alkyl halide and a non-nucleophilic base such as DIPEA, or, alternatively, by a metal-mediated

etherification with a palladium ( II) source in the presence of a dibasic ligand such as 1 , 10-phenanthroline in the presence of a non-nucleophilic base such as DIPEA or TEA using an unsymmetrical vinyl ether as the solvent. One skilled in the art will recognize that the azetidine may be protected with a wide array of protecting groups such as an alkyl group, a substituted alkyl, an aralkyl, an amide, or an alkyl carbamate. More specifically, a solution of N-BOC-3-hydroxyazetidine may be treated with palladium(II) acetate in the

presence of TEA and 4,7-diphenyl- 1 , 10-phenanthroline in n-butyl vinyl ether to give the N -protected vinyloxyazetidine (compound 7a, R1 = allyl, Scheme 2, Step A). The vinyl group may be converted to the protected 3-cyclopropoxyazetidine (compound 8) by a Simmons-Smith reaction or similar carbene-generati ng conditions, for example, using chloroiodomethane and an alkylzinc reagent in DCE, as shown in Scheme 2, Step B. Deprotection of the protected 3-cyclopropoxyazetidine (compound 8) under standard conditions as those well described in the art, followed by treatment of the free base with a solution of mineral acid in organic solvent, such as HC1 in diethyl ether or 1 ,4-dioxane, may provide the stable azetidine salt (compound 9a). More specifically, when the protecting group is BOC, one skilled in the art will recognize that treatment of the protected 3-cyclopropoxyazetidine (compound 8) with an acid such as HC1 in 1 ,4-dioxane, followed by solvent evaporation, may afford the crude 3-cyclopropoxyazetidine hydrochloride (compound 9a, Scheme 2, Step C). Additionally, the

cyclopropylmethoxyazetidine (compound 7b, R1 = cyclopropylmethyl, Scheme 2, Step A) may be prepared by alkylation of the appropriately substituted 3-hydroxyazetidine (compound 6) with bromomethylcyclopropane under strongly basic deprotonation conditions, for example, with NaH in a polar solvent such as DMF or DM SO, with subsequent deprotection of the protected cyclopropylmethoxyazetidine (compound 7b, R1 = cyclopropylmethyl) to obtain the crude cyclopropylmethoxyazetidine hydrochloride (compound 9b, Scheme 2, Step D).

Other substituted azetidines may be prepared from the commercially available benzhydryl azetidine mesylate (compound 10) by treatment with a wide variety of N, O, C and S containing nucleophiles under nucleophilic substitution conditions using an appropriate base such NaHCO?, K2C03, DIPEA or TEA and microwave heating, or by treatment with a strong base such as NaH, KOtBu or LHMDS and heating in a polar organic solvent such as DMF or DM SO, to give a substituted benzhydrylazetidine (compound 1 1 , Scheme 3, Step A). Subsequent deprotection under catalytic

hydrogenation (Scheme 3, Step B) may yield the desired substituted azetidine (compound 12).

Scheme 4

13 14 15

Step C

17 16

Scheme 4 depicts the preparation of 2-alkoxy-3-chloromethyl-4,6-dimethyl-pyridines (compound 17, where Ra is€¾,€¾€]¾, or Bn), which may be prepared starting from commercially available 3-cyano-4,6-dimethylpyridone (compound 13). Alkylation of the 3-cyano-4,6-dimethylpyridone (compound 13) with the appropriate alkyl halide under standard literature conditions known to one skilled in the art, may-provide the desired 2-alkoxy-3-cyano-4,6-dimethylpyridine (compound 14). Specifically, treatment of 3-cyano-4,6-dimethylpyridone (compound 13) with methyl iodide or benzyl chloride with AgC03 or Ag20 in an aprotic solvent such as 1 ,4-dioxane, DMF, toluene, or CHC13 with subsequent heating, may give the requisite 2-methoxy- or 2-benzyloxy-3-cyano-4,6-dimethylpyridine (compound 14, Scheme 4, Step A). Subsequent reduction of the cyano group in the 2-alkoxy-3-cyano-4,6-dimethylpyridine (compound 14) under standard conditions well known in the literature to one skilled in the art, such as slow treatment with a reducing agent such as DIBAL-H in an aprotic solvent such as DCM at 0 °C or RT may give the corresponding pyridine aldehyde (compound 15, Scheme 4, Step B). Further reduction to the carbinol (compound 16, Scheme 4, Step C) may be realized by standard conditions well known to one skilled in the art; specifically, treating the pyridine aldehyde (compound 15) portion wise with a common reducing agent such as NaBH4 at 0 °C or lower temperature, to obtain the carbinol (compound 16). Subsequent chlori nation of the carbinol (compound 16) with a typical chlorinating agent such as SOCl2 or POCI3 in an aprotic solvent such as DCM at low temperatures such as -40 °C to -60 °C may give the requisite chloromethylpyridine (compound 17, Scheme 4, Step D).

Scheme 5

18 19 20

Scheme 5 illustrates the synthesis of methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)thiophene-3-carboxylate (compound 20). As is well known in the art, the aryl bromide (compound 1 8) may be carbonylated using an array of palladium(II) catalysts and a variety of appropriate phosphine ligands, specifically palladium(ll) acetate and l,l '-bis(diphenylphosphino)ferrocene, in the presence of an alcohol such as MeOH in a polar solvent such as DMF or DMA with or without a non-nucleophilic organic base such as DIPEA or TEA, under a pressurized atmosphere of carbon monoxide, to obtain the ester (compound 19, Scheme 5, Step A). Subsequent borolane esterifi cation may be effected either by deprotonation with an alkyl metal lating reagent such as /i-butyl-, .s-butyl-, or /-butyllithium with quenching of the aryl anion with a borate ester, or by transition-metal coordination complexes using palladium(II), iridium(I), or iron(III), to obtain the desired boronic ester. Specifically, the ester (compound 19) may be treated with bis(l,5-cyclooctadiene)di^-methoxydiiridium(I) and 4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane portion wise in a nonpolar solvent such as cyclohexane with concomitant heating to obtain methyl 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)thiophene-3-carboxylate (compound 20, Scheme 5, Step B).

Scheme 6

ci

27 26 25

24

The 2-ethoxypyridine (compound 27) may be prepared according to the route depicted in Scheme 6, starting with condensation of malononitrile with acetyl ketene under basic conditions in an appropriate polar organic solvent, such as sodium hydride and THF, to obtain the 2-amino-3-cyanopyranone (compound 21 , Scheme 6, Step A). Subsequent thermal rearrangement with an inorganic acid, such as HC1, may give the 3-cyano-4-hydroxy-6-methylpyridone (compound 22, Scheme 6, Step B). Chlorination to the 4-chloropyridone (compound 23) may be effected using many chlorinating agents well known in the art, more specifically a mixture of POCl3 and PC15 (Scheme 6, Step C); alkylation of the resulting pyridone (compound 23) may be achieved via metal-mediated etherification with an alkyl halide in an appropriate non-polar organic solvent, more specifically using silver(I) oxide and iodoethane in toluene, to give the 2-ethoxy-3-cyano-4-chloropyridine (compound 24, Scheme 6, Step D). Two-step reduction using reducing agents such as DIBAL-H followed by NaBH4 or NaCNBH3 may give the alcohol

(compound 26, Scheme 6, Steps E-F), and subsequent chlorination with a chlorinating agent such as POCl3 or PCI5 in an appropriate organic solvent may yield the

ethoxypyridine (compound 27). More specifically, chlorination of the alcohol (compound 26) may be achieved via in situ preparation of the mesylate by treatment with

methansulfonyl chloride in DCM from 0 °C to RT to give the ethoxypyridine (compound 27, Scheme 6, Step G).

Scheme 7

Formula I

Scheme 7 depicts the synthesis of compounds of Formula I. Coupling of the prepared vinyl phosphate (compound 5, Scheme 1 , Step D) with the aryl boronate ester (compound 20, Scheme 5, Step B) under standard Suzuki-type coupling conditions utilizing a palladium(ii) catalyst and a phosphine ligand with a mild inorganic base such as K3PO4 in a polar organic solvent such as 1 ,4-dioxane may give the vinyl thiophene ester (compound 28, Scheme 7, Step A). Reduction of the vinyl moiety may be accomplished by procedures well documented in the art to obtain the a-methyl thiophene ester (compound 29, Scheme 7, Step B). Stereoselective reduction of the vinyl group may be achieved using an array of catalysts and ligands well documented in the art, especially with an iridium(I) catalyst/1 igand complex such as [(4R,5R)-(+)-0-[ 1 -benzyl- l-(5-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl] (dicyclohexylphosphinite) ( 1 ,5-COD) iridium(I) tetrakis (3,5-bis(trifluoromethyl) phenylborate to yield the desired stereospecific ester (compound 29). Subsequent bromination in Scheme 7, Step C, to give the 5-bromothiophene ester (compound 30), may be effected using a brominating agent such as elemental bromine or NBS in a suitable organic solvent such as CHC13, DCM, EtOAc, 1 ,4-dioxane or CC14. Alkylation to methyl 2-[2-(benzyloxycarbonylamino)ethyl]-5-[ 1 -( 1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl]-4-methyl-thiophene-3-carboxylate (compound 3 1 ) under standard palladium-mediated coupling conditions, specifically using RuPhos-G3-palladacycle (Scheme 7, Step D) followed by deprotection of the carbobenzyloxy amine (compound 3 1 ) under typical hydrogenolysis conditions well known in the art, specifically, in situ cyclization in a polar organic alcoholic solvent such as MeOH (Scheme 7, Step E) and unmasking to the ketone under standard acidic conditions, for example, using HQ in a suitable polar solvent such as THF or EtOH, may be accomplished to give 3-methyl-2-[ 1 -(4-oxocyclohexyl)ethyl]-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (compound 33, Scheme 7, Step F). Reductive animation may be effected in the presence of a Lewis acid such as titanium isopropoxide and a reducing agent such as NaBH4, Na(OAc3)BH, or NaCNBH3 in a suitable solvent such as DCM or MeOH, to obtain a mixture of the trans- and-cis- cyclohexane

(compound 34, Scheme 7, Step G), which may be separable by crystallization or chromatography methods well known in the art. Further, one skilled in the art may recognize that utilization of L1BH4 as a reducing agent may lead primarily to the trans-stereoisomer. Alkylation under well-known conditions with an appropriately substituted aralkyl halide, such as benzyl halide, followed by either demethylation or debenzylation under acidic conditions, for example using LiCl in the presence of PTSA with heating, may give the compound of Formula I (Scheme 7, Steps H and M).

Alternatively, the carbobenzyloxy amine (compound 3 1 , Scheme 7, Step D) may be subjected to hydrogenolysis using conditions well known in the art, for example with Pd(OH)2 on carbon in a suitable organic solvent such as MeOH, and hydrogenolysis may be effected in the presence of a pyridine aldehyde (e.g., compound 1 5, Scheme 4, Step B), to give methyl 5-[ 1 -( 1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl]-4-methyl-2-[2-[(6-methyl-3-pyridyl)methylamino]ethyl]thiophene-3-carboxylate (compound 35, Scheme 7, Step I). Subsequent unmasking to the ketone, reductive amination, cyclization under thermal

acidic conditions, and O-deprotection as above may yield the compounds of Formula I (Scheme 7, Steps J-M).

Alternatively, an amine such as compound 38, in which R3=H, R4= benzyl, may be subjected to hydrogenolysis using conditions well known in the art to provide an amine in which R3=R4=H. Subjecting this amine to reductive amination conditions and O-deprotection as above may yield compounds of Formula I. Specifically, use of acid, formaldehyde and triacetoxyborohydride may result in a reductive amination product in which R3=R4=Me.

Scheme 8 depicts the synthesis of compounds of Formula II. Nitration of the ester (compound 19, Scheme 5, Step A) with subsequent nitro reduction under standard conditions may yield methyl 5 -amino-4-methyl -thiophene-3 -carboxy ate (compound 40, Scheme 8, Steps A-B). Amino protection with a suitable amine protecting group, such as BOC, and subsequent alkylation under typical conditions, for example alkylating with methyl iodide in the presence of a mild base such as K2CO3 or CS2CO3 in a polar solvent such as DMF, may yield an appropriately N -alkylated protected amino thiophene, which may be followed by in situ carbamate cleavage and subsequent reductive amination, for example with a cyclohexanone, such as l,4-dioxaspiro[4.5]decan-8-one, and

Na(OAc3)BH or NaCHBH3, in a suitable organic solvent such as DCE, to obtain the requisite tertiary amine (compound 41 , Scheme 8, Step C, where R5 = CH3). Alternately, 5-amino-4-methyl-thiophene-3-carboxylate (compound 40) may first be subjected to reductive amination conditions with a cyclohexanone , such as l,4-dioxaspiro[4.5]decan-8-one, in the presence of Na(OAc)3BH or NaCNBH3 in a suitable organic solvent such as DCE, followed by a second reductive amination in situ with acetaldehyde, to obtain the requisite tertiary amine (compound 41 , Scheme 8, Step C, where R5 = CH2CH3).

Subsequent bromination, metal -mediated alkylation, cyclization to the bicyclic lactam (compound 44), lactam -alkylation, unmasking to the ketone, reductive amination and final demethylation or debenzylation all may be performed similarly to the methods of Scheme 7 to obtain the final compounds of Formula 11 (Scheme 8, steps D-J).

Alternatively, the ketal (compound 45, Scheme 8, Step G) may first be dealkylated to obtain the pyridone ketone(compound 48, Scheme 8, Step K) under similar conditions described in Scheme 7. Subsequent alkylation followed by reductive amination or double reductive amination (under conditions similar to Scheme 8, Step C) may be performed to obtain the compounds of Formula II (Scheme 8, Step L)

cheme 9

Formula ΙΠ

Scheme 9 depicts the synthesis of compounds of Formula III. An N -alkylated methyl 2-bromo-5 - [R5-( l ,4-dioxaspiro [4.5]decan-8-yl)amino] -4-methyl-thiophene-3 -carboxylate (compound 42, Scheme 8, Step D) may be alkynylated via transition-metal mediated coupling procedures well known in the art. More specifically, the

bromothiophene (compound 42) may be treated with benzyl prop-2-yn- 1 -yl carbamate in the presence of Cul, an appropriate palladium(II)-ligand complex, such as

bis(triphenylphosphine)palladium(I I) dichloride, and a non-nucleophilic organic base such as TEA, to obtain the alkyne (compound 49, Scheme 9, Step A). Subsequent reduction of the alkyne and deprotection of the amine moiety is well known in the art. Specifically, treatment of the alkyne (compound 49) under standard catalytic

hydrogenation conditions and in situ hydrogenolysis with H2 in the presence of Pd on carbon or Pd(OH)2 on carbon in a suitable organic solvent such as MeOH, EtOH, or

EtOAc under pressure, may give the amine (compound 50, Scheme 9, step B), which may be subsequently cyclized under basic conditions such as KOtBu and heating to obtain the lactam (compound 51 , Scheme 9, Step C). Alkylation of the lactam nitrogen, unmasking to the ketone, reductive animation and final dealkylation all may be performed similarly to what is described in Scheme 8 to obtain the compounds of Formula III (Scheme 9, Steps D-F).

heme 10

Formula IV

Scheme 10 depicts the synthesis of compounds of Formula IV starting with the appropriately substituted 5 -bromothiophene ester (compound 30), utilizing methods similar to those described in Scheme 9 (Scheme 10, Steps A-F).

Formula V

The preparation of compounds of Formula V is depicted in Scheme 1 1. Treating the aminothiophene (compound 40, Scheme 8, Step B) with an appropriately protected aminoalkyl ketone under reductive amination conditions well known in the art with subsequent alkylation, using an alkylating agent such as CH3I or CH3CH3I under basic conditions with an appropriate base such as NaH or K2CO3, or alkylation via a second reductive amination with, for example, acetaldehyde, (Scheme 1 1 , Step A), may give the N-alkylated N-piperidinyl thiophene ester (compound 59). More specifically, 3,4-dimethylthiophen-2-amine (compound 40) may be treated with tert-butyl-4-oxopiperidine- 1 -carboxylate in an appropriate organic solvent such as DCE with portion wise addition of a suitable reducing agent such as Na(OAc)3BH with subsequent addition of formaldehyde or acetaldehyde to obtain the N-alkylated N-piperidinyl thiophene (compound 59). Subsequent bromination, alkylation of the aryl bromide (compound 60) under Pd-catalyzed coupling conditions to obtain alkylthiophene (compound 61 ), cyclization to the lactam, lactam-N alkylation, and finally deprotection in a manner similar to that described in Scheme 8, may give compounds of Formula V (Scheme 1 1 , Steps B-F).

Scheme 1 2

Scheme 12 shows the synthesis of compounds of Formula VI. Double alkylation of the aminothiophene (compound 40) under reductive animation conditions, specifically using first an appropriately protected 4-aminocyclohexanone and then acetaldehyde in the presence of Na(OAc)3BH, may give the N-alkylated thienylcyclohexylamine (compound 64, Scheme 12, Step A). Additionally, N-methylation to this N-alkylated

thienylcyclohexyl amine (compound 64) may be effected by first protecting the amino thiophene with an appropriate amine protecting group, such as BOC, followed by treatment of the subsequent carbamate with a strong base, such as NaH or KOtBu, treatment of the resulting anion with an alkyl halide such as CH3I, removal of the amine protecting group, and finally reductive animation with an appropriately protected 4-aminocyclohexanone. Deprotection of the cyclohexylamino group yielding the 4-aminocyclohexane (compound 65) may be accomplished readily via an array of conditions well recognized to one skilled in the art (Scheme 12, Step B). Alkylation (Scheme 1 2, Step C) of this 4-aminocyclohexane (compound 65, Scheme 12, Step C) may be effected using the in .s/' w-generated triflate of 2-methoxypropane- 1 ,3-diol (compound 66), and subsequent bromination, using either elemental bromine or N BS, gives the bromothiophene (compound 69, Scheme 12, Step E). Alkylation of the arylbromide (compound 69) under palladium catalyzed conditions, for example using a substituted

potassium trifluoroborate salt with catalytic RuPhos-G3-Palladacycle in a mixture of toluene and water in the presence of an inorganic base such as K2CO3 and heating, may result in the -alkylated methyl 2-[2-(benzyloxycarbonylamino)ethyl]-5-[[4-(3-methoxyazetidin-l-yl)cyclohexyl]amino]-4-methyl-thiophene-3-carboxylate (compound 70, Scheme 12, Step F). Deprotection under conditions well described in the art, with concomitant reductive amination in situ using an appropriately substituted heteroaryl aldehyde, for example, in the presence of Pd(OH)2 on carbon in an alcoholic solvent, such as EtOH, under pressure and heating, may give the substituted aminomethy pyridine (compound 71, Ra = CH3 or Bn, Scheme 12, Step G). Subsequent cyclization and deprotection under conditions similar to those described in Scheme 8, may yield compounds of Formula VI (Scheme 12, Steps H-I).

Scheme 13

Formula II

Scheme 13 depicts an alternative synthesis of compounds of Formula II. Unmasking the ketal (compound 42, Scheme 8, Step D) under acidic conditions similar to those described in Scheme 7, Step J or Scheme 8, Step K, may give the corresponding ketone (compound 73, Scheme 13, Step A). Double reductive amination under conditions similar to Scheme 8, Step L, may result in the cyclohexyl amine (compound 74, Scheme 13, Step B), and subsequent transition-metal mediated coupling under conditions described in Scheme 7, Step D, followed by amine deprotection well described in the literature, may give aminocyclohexane (compound 75, Scheme 13, Step C). Cyclization to the 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (compound 76) under similarly described conditions in Scheme 1 1 , Step D, followed by alkylation conditions similarly described in Scheme 7, Step H, may give the substituted pyridine (compound 77, Scheme 13, Step E), and final dealkylation under similarly described conditions in Scheme 7, Step M, may result in the compound of Formula II (Scheme 13, Step F).

heme 14

Scheme 14 illustrates an alternative synthetic pathway to compounds of Formula IV. The alkyne compound 54 (Scheme 10, step A) may be simultaneously reduced and deprotected using an array of techniques well known in the art, such as catalytic hydrogenation with palladium(II) hydroxide, and in situ reductive amination with an appropriately substituted 2-alkoxypyridine, such as 4,6-dimethyl-2-alkoxypyridine, maybe accomplished under conditions similar to those depicted in Scheme 9, step B to give ketal compound 78. Subsequent unmasking to the ketone compound 79, cyclization to the lactam compound 80, reductive amination with an appropriately substituted amine to obtain compound 81 , and final dealkylation, all under similarly described conditions depicted in Scheme 7 (steps J-M), may yield compounds of Formula IV.

One skilled in the art will recognize that separation of all relevant trans- and cis-isomers described in Schemes 7- 12 may be accomplished using standard techniques well known in the art, for example, either by using standard flash chromatography on silica and an appropriate organic solvent mixture (e.g., EtOAc/hexanes) or by reverse phase chromatography over C- 18 silica using an appropriate water/organic solvent mixture (e.g., H20 buffered with NH4OAc or N H4HCO and ACN).

Add tert-butyl 3-hydroxyazetidine- 1 -carboxylate ( 12.0 g, 69.3 mmol), n-butyl vinyl ether ( 125.0 mL, 961 mmol), and TEA (4.1 mL, 29 mmol) to a sealed flask. Bubble the mixture with N2 vigorously for 10 min. Add 4,7-diphenyl- 1 , 10-phenanthroline ( 1 .0 g, 2.92 mmol) and Pd(OAc)2 (0.66 g, 2.91 mmol). Seal the flask and stir the mixture under NT at 80 °C for 7 days. Filter the mixture through diatomaceous earth and rinse the filter cake with EtOAc. Concentrate the filtrate and subject the resulting residue to

chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes, to give the title compound (9.95 g, 72% yield) as yellow oil after solvent evaporation. Ή NMR

(400.1 MHz, CDCI3) δ 1.44 (s, 9H), 3.90 (dd, J= 4.2, 10.1 Hz, 2H), 3.97 (dd, J = 2.5, 14.5 Hz, 1 H), 4.08 (dd, J= 2.5, 6.8 Hz, 1 H), 4.17 (dd, J= 6.5, 10.1 Hz, 2H), 4.55-4.61 (m, 1 H), 6.37 (dd, J = 6.8, 14.5 Hz, 1 H).

Preparation 2

tert-Butyl 3-(cyclopropoxy)azetidine- 1 -carboxylate

Cool a solution of tert-butyl 3-vinyloxyazetidine- 1 -carboxylate (9.9 g, 50 mmol) and chloroiodomethane (12 mL, 159.8 mmol) in DCE (50 mL) to -5 °C, and then add a solution of \ M diethylzinc in heptane (80 mL, 80 mmol) drop wise over 60 min while maintaining the internal temperature between 0 and -5 °C. Warm to RT and stir the mixture for 30 min. Re-cool the mixture in an ice bath and quench the reaction with saturated aqueous NH4C1 solution. Add concentrated N H4OH solution, and then extract the resulting mixture three times with MTBE. Wash the combined extracts with saturated aqueous NH4C1 solution, dry over anhydrous K2C03, filter, and concentrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes, to give the title compound (4.90 g, 46% yield) as colorless oil after solvent evaporation. Ή NMR (400.1 MHz, CDC13) δ 0.45-0.50 (m, 2H), 0.57-0.62 (m, 2H), 1 .43 (s, 9H), 3.21 -3.26 (m, 1H), 3.85 (dd, J = 4.2, 9.8 Hz, 2H), 4.08 (dd, J = 6.6, 9.8 Hz, 2H), 4.32 (m, 1 H).

Preparation 3

3-(Cyclopropoxy)azetidine hydrochloride

O

Cl H

Cool a solution of tert-butyl 3-(cyclopropoxy)azetidine- 1 -carboxylate (4.45 g, 20.9 mmol) in THF ( 10 mL, 123 mmol) in an ice bath and drop wise add a solution of 4N HCl in 1 ,4-dioxane (20 mL, 80 mmol). Stir the solution at RT for 3 hr and concentrate in vacuo. Dissolve the residue in 2-propanol, concentrate, and dry in vacuo to give the title compound (3.0 g, 96% yield) which may be used without additional purification. Ή NMR (400.1 MHz, CD3OD) δ 0.48-0.54 (m, 2H), 0.56-0.61 (m, 2H), 3.35-3.40 (m, 1H), 3.98 (dd, J= 4.8, 1 1 .8 Hz, 2H), 4.29 (dd, J = 6.8, 1 1.8 Hz, 2H), 4.5 1 -4.58 (m, 1H).

Preparation 4

1 -Benzhydryl-3-[(3S)-tetrahydrofuran-3-yl]oxy-azetidine

Heat a mixture of (3S)-tetrahydrofuran-3-ol ( 10 mL, 122.0 mmol) and 1 -benzhydrylazetidin-3-yl methanesul fonate (3.0 g, 9.3 mmol) at 100 °C in a microwave for 20 min. Cool the mixture to RT and dilute with EtOAc and saturated aqueous Na2C03 solution. Separate the layers, wash the organic layer sequentially with water and saturated aqueous NaCl, and dry over Mg2S04. Filter and concentrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 10-30% EtOAc in hexanes to give the title compound (0.9 g, 30% yield) as colorless oil after solvent evaporation. ES/MS (m/z): 310 (M+H).

Prepare Preparation 5 essentially by the method of Preparation 4 using (3R)-tetrahydrofuran-3-ol.

Preparation 6

3-[(3S)-Tetrah drofuran-3-yl]oxyazetidine

Flush N2 through a mixture of 1 -benzhydryl-3-[(3S)-tetrahydrofuran-3-yl]oxy-azetidine (0.85 g, 2.7 mmol), MeOH (20 mL), EtOAc (5 mL) and AcOH ( 1 mL) for 10 min. Add 10% Pd on carbon (0.50 g) and stir the resulting slurry under H2 at 60 psi for 1 8 hr. Remove the catalyst by filtration and rinse the filter cake with MeOH.

Concentrate and dry the residue in vacuo to give the title compound (0.39 g, 95% yield) suitable for use without further purification. Ή NMR (400.1 MHz, CDC13): δ 1.85-2.05 (m, 2H), 2.05 (bs, 1 H), 3.58-3.72 (m, 5H), 3.74 (d, 1 H), 3.80 (m, 1 H), 3.89 (m 1 H), 4.07 (m, 1 H), 4.34 (m, H).

Prepare Preparation 7 essentially by the method of Preparation 6 using 1 -benzhydryl-3-[(3R)-tetrahydrofuran-3-yl]oxy-azetidine.

Preparation 8

1 -[ 1 -(D din-

To a sealed tube, add to a solution of ( 1 -benzhydrylazetidin-3-yl)

methanesul fonate (7 g, 22.05 mmol) in DMF ( 15 mL), 3-methyl- l H-pyrazole (2.17 g, 26.47 mmol) and Cs2C03 (8.6 g, 26.47 mmol) and stir the mixture at 120 °C for 24 hr. Cool to RT, pour the mixture into ice water, and extract with a solution of 5% MeOH in DCM. Separate the layers, dry the organic phase over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica gel, eluting with a gradient of 7-30% EtOH in hexanes, to afford the title compound as a mixture of regioisomers as yellow oil (3.5 g, 49% yield) after solvent evaporation. ES/MS (m/z): 304 (M+H).

Prepare the following compounds essentially by the method of Preparation 8.

Preparation 1 1

1 -(Azetidin-3-yl)-3 -yl)-5-methyl-pyrazole

To a 300 mL Parr autoclave, add a mixture of l-[l-(diphenylmethyl)azetidin-3-yl]-3-methyl- 1 H-pyrazole (3.5 g, 1 1 .5 mmol) and 1 -( 1 -benzhydrylazetidin-3-yl)-5-methyl-pyrazole (mixture of regioisomers) with 10% Pd on carbon (3.5 g, 1 g/g) to a solution of MeOH (75 mL) and EtOAc (25 mL). Purge the vessel three times with H2, charge to 50 psi of H2, and stir vigorously at RT for 24 hr. Filter through a bed of diatomaceous earth and concentrate the filtrate in vacuo to afford the title compound as a mixture of regioisomers as colorless oil ( 1.58 g, 93% yield). ES/MS (m/z): 138 (M+H).

Prepare the following compounds essentially by the method of Preparation 1 g the corresponding 1 -(diphenylmethyl)azetidine.

Preparation 14

tert-Butyl 3-(cyclopropylmethoxy)azetidine- 1 -carboxylate

Add NaH (60% in oil, 900 mg, 22.5 mmol) to a solution oftert-butyl 3-hydroxyazetidine- 1 -carboxylate (3 g, 17.32 mmol) in DMF ( 10 mL) at 0 °C. Stir the mixture at RT for 1.5 hr, then slowly add bromomethylcyclopropane (2.80 g, 20.7 mmol) and stir over 72 hr. Dilute the mixture with EtOAc and Et20, wash twice with water, once with saturated aqueous NaCl, separate the layers, dry the organic extract over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes to give the title compound ( 1 .91 g, 48% yield) as colorless oil after solvent evaporation. Ή NMR (400.1 MHz, CDCI3) δ 0.1 8-0.22 (m, 2H), 0.54-0.58 (m, 2H), 1 .00- 1 .04 (m, 1 H), 1.43 (s, 9H), 3.23 (d, J= 7.0 Hz, 2H), 3.85 (dd, J= 4.3, 10.1 Hz, 2H), 4.06 (dd, J= 6.5, 10.1 Hz, 2H), 4.20-4.26 (m, 1 H).

Preparation 15

3 -(Cyclopropylmethoxy)azetidine hydrochloride

H

Add a 4N HC1 solution in 1 ,4-dioxane ( 15 mL, 60 mmol) to tert-butyl 3-(cyclopropylmethoxy)-azetidine- 1 -carboxylate ( 1 .91 g, 8.40 mmol) in a round bottom flask and stir at RT overnight. Concentrate the reaction mixture in vacuo and dry the resulting residue in vacuo to give the title compound ( 1.68 g, quantitative yield), suitable for use without further purification. Ή NMR (400.1 MHz, DMSO-de) δ 0. 14-0.1 8 (m, 2H), 0.44-0.48 (m, 2H), 0.91 -0.99 (m, 1 H), 3.21 (d, J= 7.0 Hz, 2H), 3.72-3.82 (m, 2H), 4.02-4.12 (m, 2H), 4.30-4.37 (m, 1 H), 9.17 (bs, 2H).

Preparation 16

2-methoxy-4,6-dimethyl-pyridine-3-carbonitrile

Add a solution of NaOCH3 in MeOH (30 mass%, 175 mL, 940 mmol) drop wise to a solution of 2-chloro-4,6-dimethyl-pyridine-3-carbonitrile (75 g, 441.1 mmol) in MeOH (450 mL) in a water bath followed by another drop wise addition of NaOCH3 in MeOH (25 mass%, 250 mL, 1090 mmol). Stir the resulting mixture for 1 hr, pour in ice cold water, stir for 30 min, and filter the resulting solid. Wash filter cake with hexane and dry in a vacuum oven overnight. Extract the aqueous filtrate with DCM, dry the organic phase over MgS04, filter and concentrate in vacuo. Combine the filtered solid and the

evaporated residue to afford title compound as a solid (71.8 g, quantitative yield). ES/MS (m/z): 163 (M+H).

Preparation 17

2-methoxy-4,6-dimethyl-pyridine-3-carbaldehyde

Add a \ M solution of DIBAL-H in toluene (240 mL, 240 mmol) to a solution of 2-methoxy-4,6-dimethyl-pyridine-3-carbonitrile (48 g, 295.95 mmol) in DCM (480 mL) at 0 °C over 2 hr. Remove the ice bath after 1 hr and stir at RT overnight. Cool in a water bath at RT and quench by slowly adding a mixture of 1 M aqueous HC1 ( 192 mL) and AcOH ( 192 mL). Add DCM, separate the layers, wash the organic phase with saturated aqueous NaCl, dry over Na2S04, filter and concentrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc/hexane to afford title compound as a solid (22.6 g, 46% yield) after solvent evaporation. ES/ S (m/z): 166 (M+H). Ή NMR (400.1 MHz, CDC13) δ 2.43 (s, 3H), 2.54 (s, 3H), 4.01 (s, 3H), 6.61 (s, 1 H), 10.48 (s, 1 H).

Preparation 1 8

(2-Methoxy-4,6-dimethyl-3-pyridyl)methanol

Add aBH4 (6.4 g, 170 mmol) portion wise to a solution of 2-methoxy-4,6-dimethyl-pyridine-3-carbaldehyde (22.6 g, 137 mmol) in MeOH (500 mL) at 0 °C. Warm the solution to RT and stir overnight. Add additional NaBH4 ( 1 .0 g) and stir the mixture for 1 hr. Cool the flask to 0° C, add ice-cold water (50 mL), and concentrate the resulting mixture to ~ ½ volume in vacuo. Add saturated aqueous NaHC03 to the resulting residue, extract with DCM, separate the layers, wash the organic phase with saturated aqueous

NaCl, and dry the organic phase over Na2S04. Filter and concentrate the filtrate in vacuo to afford the title compound as oil (23 g, quantitative yield). ES/MS (m/z): 168 (M+H).

Preparation 19

3-(Chloromethyl)-2-methoxy-4,6-dimethyl-pyridine

Add a solution o f methanes ul fony 1 chloride (22 mL, 281 mmol) dissolved in DCM ( 100 mL) to a solution of (2-methoxy-4,6-dimethyl-3-pyridyl)methanol (39 g, 233.25 mmol) in DCM (500 mL) containing DIPEA (54 mL) at 0 °C. Warm slowly to RT and stir over about 48 hr. Concentrate the reaction mixture in vacuo and subject the resulting residue to chromatography on silica, eluting with a gradient of 2-5%

EtOAc/hexane, to afford the title compound as a solid (30.85 g, 71% yield) after solvent evaporation. H 1 NMR (399.8 MHz, DMSO-de): 2.28 (s, 3H), 2.30 (s, 3H), 3.84 (s, 3H), 4.69 (s, 2H), 6.70 (s, 1 H).

[Reparation 20

2-(Benzyloxy)-4,6-dimethylpyridine-3-carbonitrile

Drop wise add benzyl chloride ( 100 mL, 859.5 mmol) to a mixture of 2-hydroxy-4,6-dimethyl-pyridine-3-carbonitrile ( 100 g, 675 mmol) and silver oxide ( 174 g, 747 mmol) in toluene ( 1 L) in a 2-L three-neck flask equipped with a mechanical stirrer. Stir the mixture at 1 10 °C for 6 hr. Cool the mixture to ~60 °C, filter over diatomaceous earth, rinse with DCM and concentrate the filtrate in vacuo. Dissolve the crude product in DCM and drop wise add MeOH until a solid appears. Filter and collect the resulting solid to give the title product as a brown solid ( 144.9 g, 90% yield). ES/MS (m/z): 239 (M+H).

Preparation 21

2-(Benzyloxy)-4,6-dimethylpyridine-3-carbaldehyde

Drop wise add a solution of \ M DIBAL-H in toluene (200 mL, 200 mmol) to a solution of 2-(benzyloxy)-4,6-dimethylpyridine-3-carbonitrile (40.3 g, 169 mmol) in DCM (400 mL) at 0 °C over 3 hr. Warm the reaction mixture to RT, and stir for 3 hr. Very slowly quench the reaction with a 1 : 1 mixture of IN HC1 ( 160 mL) and acetic acid ( 160 mL) at RT. Add saturated aqueous NaCl ( 100 mL) and extract with DCM. Separate the layers and dry the organic extracts over Na2S04 overnight. Filter, concentrate the filtrate in vacuo, and subject the resulting residue to chromatography on silica, eluting with a gradient of 0-5% EtOAc in hexanes, to obtain the title compound (24.47 g, 60% yield) after solvent evaporation. ES/MS (m/z): 242 (M+H).

Preparation 22

(2-Benzyloxy-4,6-dimethyl-3-pyridyl)methanol

Dissolve 2-(benzyloxy)-4,6-dimethylpyridine-3-carbaldehyde (46.5 g, 193 mmol) in MeOH ( 1 L) in a 2-L three-neck flask in an ice bath equipped with a mechanical stirrer and add NaBH4 (8.7 g, 230 mmol) in small portions over 1 hr. Warm the mixture to RT and stir for 3 hr. Re-cool the mixture to 0 °C and quench with ice-cold water (50 mL). Concentrate the reaction mixture in vacuo and add saturated aqueous NaHC03 solution.

Extract three times with DCM, wash the combined extracts with saturated aqueous NaCl, and dry
Filter and concentrate the filtrate in vacuo to give the title compound (46.8 g, 99.8% yield) as colorless oil. ES/MS (m/z): 244 (M+H).

Preparation 23

2-Benzyloxy-3-(chloromethyl)-4,6-dimethyl-pyridine

Add SOCl2 (4.0 g, 33 mmol) slowly to a solution of (2-benzyloxy-4,6-dimethyl-3-pyridyl)methanol (6.0 g, 25 mmol) in DCM (100 mL) at -60 °C under N2 and then warm to -40 °C for 30 min. Pour the cold reaction mixture into ice/water ( 100 mL). Adjust the pH of the mixture with saturated aqueous NaHCC until slightly basic, then sequentially extract the aqueous mixture twice with DCM, combine the organic extracts, and dry over MgS04. Filter and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-30% EtOAc in hexanes to give the title compound (4.90 g, 76% yield) as a white solid. Ή NMR (400.1 MHz, CDC13) δ 2.35 (s, 3H), 2.40 (s, 3H), 4.71 (s, 2H), 5.43 (s, 2H), 6.61 (s, 1 H), 7.28-7.33 (m, 1 H), 7.35-7.40 (m, 2H), 7.47-7.51 (m, 2H).

Preparation 24

2-Amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile

Cool a suspension of NaH (85.4 g, 2.10 mol) in anhydrous THF (0.70 L) to 0 °C. Add neat malononitrile (238 g, 3.6 mol) drop wise to the stirred suspension. Stir at 0 °C for 10 min, then cool to - 10 °C and add a solution of acetyl ketene ( 163 g, 1 .91 mol) in THF (0.6 L) drop wise. Stir at - 10 to 0 °C for 1 hr, then neutralize using concentrated HC1 and dilute with water ( 1.0 L). Stir at RT for 16 h. Collect the solid by filtration and air dry to give yellow solid. Recrystallize from EtOH to obtain the title compound as a yellow powder ( 120 g, 42% yield). Ή NMR (400.1 MHz, DMSO-de) δ 2.15 (3H, s) 5.87 ( 1 H, s), 8.50 (2H, s).

Preparation 25

4-Hydroxy-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 -carbonitrile

Heat a suspension of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile ( 120 g, 0.80 mol) in 10% aqueous HCl ( 1 .0 L) at 100 °C for 12 hr with stirring. Cool to RT and concentrate under reduced pressure. Add EtOH (0.40 L) to the resulting residue and collect the solid by filtration to afford the title compound as a white solid ( 103 g, 86% yield). Ή NMR (400.1 MHz, DMSO-d6,) δ 2.15 (3H, s), 5.87 ( l H, s), 1 1.68 ( l H, s), 12.49 (bs).

Preparation 26

4-Chloro-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 -carbonitrile

Suspend 4-hydroxy-6-methyl-2-oxo- 1 ,2-dihydropyridine-3-carbonitrile ( 103 g, 0.69 mol) in CHC13 (1.0 L) and add phosphoryl chloride (210 g, 1.37 mol) and phosphorus pentachloride (286 g, 1 .37 mol). Heat at 70 °C for 8 hr with stirring. Cool to RT, slowly pour into ice-water with vigorous stirring, neutralize the mixture using concentrated aqueous NH3, and collect the resulting precipitate by filtration to afford the title compound as a brown solid (77 g, 65% yield) after drying in a vacuum oven. Ή NMR (DMSO-de, 400.1 MHz, ppm) δ 2.27 (3H, s), 6.50 (1H, s).

Preparation 27

4-Chloro-2-ethoxy-6-methylpyridine-3-carbonitrile

Add iodoethane (3.3 mL, 41 mmol) to a mixture of 4-chloro-6-methyl-2-oxo- 1 H-pyridine-3-carbonitrile (4.6 g, 27 mmol) and Ag20 ( 13 g, 55.8 mmol) in toluene (250 mL) and stir the resulting mixture at reflux for 4 hr. Cool the mixture to 60 °C, filter through diatomaceous earth, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 100% EtOAc in hexanes, to afford the title compound (2.5 g, 47% yield) as a white solid after solvent evaporation. ES/MS (m/z): (35C1/37C1) 197/199 (M+H).

Preparation 28

4-Chloro-2-ethoxy-6-methylpyridine-3-carbaldehyde

Add \ M DIBAL-H in toluene (18 mL, 1 8 mmol) to a solution of 4-chloro-2-ethoxy-6-methylpyridine-3-carbonitrile (2.2 g, 1 1 mmol) in DCM ( 100 mL) drop wise at 0 °C. Gradually warm the mixture to RT, stir overnight, place the flask in a water bath at RT, and quench the reaction by adding a mixture of 1 M aqueous HCl (9 mL) and AcOH (9 mL) drop wise. Dilute the resulting mixture with DCM, separate the resulting layers, wash the organic extract with saturated aqueous NaCl, and dry the organic extract over anhydrous Na2S04. Filter and concentrate the filtrate in vacuo to afford the title compound ( 1.7 g, 76% yield) as an orange solid. ES/MS (m/z): (35C1/37C1) 200/202

(M+H).

Preparation 29

(4-Chloro-2-ethoxy-6-methylpyridin-3-yl)methanol

Add NaBH4 (0.230 g, 6.08 mmol) to a solution of 4-chloro-2-ethoxy-6-methylpyridine-3-carbaldehyde ( 1 g, 5 mmol) in MeOH (50 mL) at 0 °C. Gradually warm the mixture to RT, stir for approximately 2 hr, quench the mixture with saturated aqueous NaHC03 solution, concentrate the mixture in vacuo, dilute the resulting residue with saturated aqueous NaHC03 solution, and extract with DCM. Separate the layers, dry the organic layer over anhydrous Na2S04, filter, and concentrate the filtrate in vacuo to afford the title compound ( 1 .03 g, 82% yield) as yellow oil. ES/MS (m/z): (35C1/37C1) 202/204 (M+H).

Preparation 30

4-Chloro-3-(chloromethyl)-2-ethoxy-6-methylpyridine

Add DIPEA (0.762 mL, 4.33 mmol) to a RT solution of (4-chloro-2-ethoxy-6-methylpyridin-3-yl)methanol ( 1 .03 g, 4.09 mmol, 80% purity) in DCM (40 mL). Cool the solution to 0 °C, then add methanesulfonyl chloride (0.335 mL, 4.28 mmol) drop wise. Gradually warm the solution to RT, stir the resulting mixture at RT for about 3 hr, and concentrate the mixture in vacuo. Add saturated aqueous NaHC03 solution and extract with EtOAc. Separate the layers, dry the organic extract over anhydrous Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to

chromatography on silica, eluting with a gradient of 5-30% EtOAc in hexanes, to afford the title compound (0.788 g, 88% yield) as yellow oil after solvent evaporation. Ή NMR δ (400.1 MHz, DMSO): 1.31 (t, J= 7.0 Hz, 3H), 2.37 (s, 3H), 4.37 (q, J= 7.0 Hz, 2H), 4.71 (s, 2H), 7.05 (s, 1 H).

Preparation 3 1

1 ,4-Dioxaspiro[4.5]decane-8-carboxylic acid

Add triethyl orthoformate (2.35 kg, 2.65 L, 15.9 mol), PTSA (2.8 g, 16 mmol) and ethylene glycol ( 1 .64 kg, 26.4 mol) to a solution of ethyl 4-oxocyclohexanecarboxylate (900 g, 5.29 mol) in EtOH (4 L) and stir the mixture at 50 °C for 1 hr. Cool to RT and slowly add a 5M aqueous solution of NaOH (4.24 L, 21.18 mol) over 20 min; stir the resulting mixture for 2 hr. Evaporate most of the EtOH under reduced pressure, add water (5 L) and MTBE (4 L), stir, separate phases, and discard the organic phase. Cool the aqueous phase to 15 °C and acidify by slow addition of 5 aqueous HCl until pH~3.3 (~ 3.7 L). Add DCM (8 L), separate the layers, dry the organic phase over Na2S04, filter, and concentrate the filtrate in vacuo to give the title compound as viscous oil that slowly solidifies on standing as a white low-melting solid (887 g, 90% yield), suitable for use in the next step without further purification. (GC-MS) MS (m/z): 99 (M-87).

Preparation 32

N-Methoxy-N-methyl- 1 ,4-dioxaspiro[4.5]decane-8-carboxamide

Slowly add CD I (915 g, 5.64 mol) in small portions over 20 min to a solution of l,4-dioxaspiro[4.5]decane-8-carboxylic acid (988.6 g, 5.3 1 mol) in DCM ( 10 L) and stir for 1 hr. Add N-methoxymethanamine hydrochloride (577 g, 5.92 mol) in small portions over 15 min and stir for 12 hr. Add more N -methoxymethanamine hydrochloride (53 g, 0.55 mol) and stir for an additional 12 hr. Add water ( 10 L), separate phases, wash the organic phase sequentially with water (5 L) and saturated aqueous NaCl (5 L), dry over Na2S04, filter, and concentrate the filtrate in vacuo to obtain the title compound as colorless oil ( 1 .24 kg, quantitative yield) suitable for use in the next step without additional purification. ES/MS (m/z): 230 (M+H).

Preparation 33

1 -( 1 ,4-Dioxaspiro[4.5]dec-8-yl)ethanone

Cool a solution of N-methoxy-N-methyl-l,4-dioxaspiro[4.5]decane-8-carboxamide (400 g, 1.74 mol) in THF (3.5 L) to 0 °C under N2 and add 3 MeMgBr solution in Et20 (697.87 mL, 2.1 mol) over 30 min. Stir for 30 min while warming to RT. Quench the reaction by slow addition of aqueous saturated NH4C1 ( 1 L) and extract with MTBE (500 mL x 3). Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry over Na2S04, filter, and concentrate the filtrate in vacuo to obtain the crude title compound as light yellow oil (275 g, 86% yield), suitable for use without further purification. (GC-MS) MS (m/z): 184 (M+).

Preparation 34

1 -( 1 ,4-Dioxaspiro[4.5]dec-8-yl)ethenyl diphenyl phosphate

Cool a solution of 1 -( 1 ,4-dioxaspiro[4.5jdec-8-yl)ethanone ( 150 g, 0.81 mol) in

THF (1 L) to -70 °C and drop wise add a solution of \ M Li HMDS in THF (896 mL, 0.89 mol) over 30 min. Stir the mixture for 15 min at -60 °C and then drop wise add diphenyl phosphorochloridate (240.6 g, 896 mmol) in THF (450 mL) at -70 °C. Stir the reaction mixture for 14 hr while warming to RT. Quench the reaction with saturated aqueous

NaHC03 solution ( 1 L) and stir for 1 hr. Extract with MTBE (8 L x 3), separate the layers, dry the combined organic extracts over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 2-33 % EtOAc in hexanes, to afford the title compound as yellow oil ( 190 g, 56% yield) after solvent evaporation. ES/MS (m/z): 417 (M+H).

Preparation 35

Methyl 4-methylthiophene-3 -carboxylate

Mix 3-bromo-4-methylthiophene (200 g, 1.13 mol), MeOH (800 mL), DMA

( 1200 mL), TEA (390 mL, 2.8 mol) and purge with nitrogen for 10 min. Add 1,1'-bis(diphenylphosphino) ferrocene (50 g, 0.09 mol) and palladium (II) acetate (20 g, 0.09 mol) and stir under CO atmosphere at 60 psi for 30 hr at 80 °C. Cool the mixture to RT, dilute with EtOAc, wash sequentially with water and saturated aqueous NaCl, and dry the organic phase over Na2S04. Filter, and concentrate the filtrate in vacuo to afford the title compound (360 g) as yellow oil, sufficient for use without additional purification.

ES/MS (m/z): 157 (M+H).

Alternative Preparation of Methyl 4-methylthiophene-3-carboxylate Dissolve 3-bromo-4-methylthiophene ( 1 .00 kg, 5.65 mol) and TEA ( 1 .43 kg,

14.12 mol) in DMA (2.5 L) and MeOH ( 1 .32 L) and add 1 , 1 -bis-diphenylphophinoferrocene ( 1 87.9 g, 0.34 mol) followed by Pd(OAc)2 (63.4 g, 0.28 mol). Stir the resulting mixture under an atmosphere of CO at 50 psi at 80 °C for 16 hr. After cooling to RT, add EtOAc (5 L), wash sequentially with 10% aqueous citric acid solution ( 1 .6 L X 2), saturated aqueous NaHC03 solution ( 1.6 L x 2), water ( 1.2 L x 2) and saturated aqueous NaCl ( 1 L x 2). Separate the layers, dry the organic phase over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with 5% EtOAc in hexanes, to give the title compound as yellow oil (653 g, 74% yield) after solvent evaporation. ES/MS (m/z): 157 (M+H).

Preparation 36

Methyl 4-methyl-5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate

Mix methyl 4-methylthiophene-3-carboxylate (250 g, 1.60 mol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (8.59 g, 32.01 mmol) and [IrMeO(COD)]2 (5.37 g, 8.00 mmol) in cyclohexane (2.5 L). Degas the mixture under vacuum, purge thoroughly with N2, and then add 4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (409.67 g, 3.20 mol) in small portions over 1 hr. Stir the resulting mixture at 70 °C for 3 hr. Cool the mixture to RT, concentrate in vacuo, and subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 1 % EtOAc in hexanes, to obtain the title compound as a solid (300 g, 66% yield) after solvent evaporation. ES/MS (m/z): 283 (M+H).

Preparation 37

Methyl 5-[ 1 -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethenyl]-4-methylthiophene-3-carboxylate

Stir a mixture of l-(l,4-dioxaspiro[4.5]dec-8-yl)ethenyl diphenyl phosphate (240 g, 576.37 mmol), methyl 4-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate (21 1.4 g, 749.28 mmol) and an aqueous solution of 2 Κ3Ρ04 (367 g, 1 .73 mol) in dioxane (2.4 L) at RT. Add chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1. 1 '-bipheny )[2-(2'-amino- 1. 1 '-biphenyl)]palladium(II) (9.07 g, 1 1.53 mmol) and stir at 80 °C for 3 hr. Evaporate the solvent under reduced pressure, extract with EtOAc (750 mL x 2), separate the layers, sequentially wash the combined organic phases with water ( 150 mL) and saturated aqueous NaCl, dry over Na2S04, filter, and

concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with 5% EtOAc in hexanes, to afford the title compound as a solid (375 g, 67% yield) after solvent removal. ES/MS (m/z): 323 (M+H).

Preparation 38

Methyl 5-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate

Add [(4R,5R)-(+)-0- [ 1 -benzyl- 1 -(5 -methyl-2-phenyl -4,5 -dihydrooxazol-4-yl)-2-phenyl ethyl j (dicyclohexylphosphinite) ( 1 ,5-COD) iridium(I) tetrakis (3,5-bis(trifluoromethyl) phenyl borate ( 1 .61 g, 0.93 mmol) to a solution of methyl 5-[ l -( l ,4-dioxaspiro[4.5]dec-8-yl)ethenyl]-4-methylthiophene-3-carboxylate (60 g, 1 86 mmol) in DCM ( 1 .9 L) and elute the solution through a 48 mL stainless steel reactor at a hydrogen atmosphere of 80 parr at 12 mL/min for 2 hr at RT. Filter the solution and concentrate the filtrate in vacuo to obtain the crude title compound as brown oil (60 g, quantitative yield), suitable for use in the next step without further purification. ES/MS (m/'z): 325 (M+H).

Preparation 39

Methyl 4-methyl-5-[(lR)-l-(4-oxocyclohexyl)ethyl]thiophene-3-carboxylate

Add to a solution of methyl 5-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate (64.7 g, 178 mmol) in THF (450 mL) a solution of IN HCl (450 mL, 5.53 mol) and stir for 16 hours at RT followed by 45 °C for 2 hours. Concentrate the reaction mixture in vacuo, add MTBE (500 mL) and separate phases. Wash the organic phase sequentially with water (200 mL), saturated aqueous NaHC03

solution ( 100 mL) and saturated aqueous NaCl ( 100 mL). Dry the organic phase over MgS04, filter, and concentrate the filtrate in vacuo to give the crude title compound as brown oil (53.3 g, 96% yield) which may be used without additional purification. ES/MS (m/z): 281 (M+H).

Preparation 40a

Methyl 5-[(lR)-l-[trans-4-(3-methoxyazetidin-l-yl)cyclohexyl]ethyl]-4- methylthiophene-3-carboxylate

Stir a solution of 3-methoxyazetidine hydrochloride (43.4 g, 35 1 mmol) and

DIPEA (65 mL, 373 mmol) in MeOH (500 mL) for 45 min at RT. Add this mixture to a solution of methyl 4-methyl-5-[( 1 R)- 1 -(4-oxocyclohexyl)ethyl]thiophene-3 -carboxylate (50.0 g, 160 mmol) in THF (250 mL) and stir 40 min at RT. Cool the mixture at -70 °C and add LiBH4 (4.9 g, 220 mmol) in five portions over 25 min. Allow to stir for 4 hr while warming to -20 °C. Pour the mixture slowly into an aqueous solution of 1 M HC1 (500 mL) and stir for 10 min. Evaporate most of the organic solvent in vacuo, add DCM (500 mL) and an aqueous solution of 5MK2CO3 (~ pH 9), separate the layers, and wash the aqueous phase again with DCM (250 mL). Combine the organic extracts, wash with saturated aqueous NaCl, dry the organic phase over MgS04, filter, and concentrate the filtrate in vacuo. Add EtOAc (50 mL) and concentrate in vacuo again. Subject the resulting residue to chromatography on silica, eluting with 20% EtOAc in 2%

triethylamine/hexanes to give oil after solvent evaporation. Dissolve the resulting oil in MTBE (200 mL), wash with aqueous 1 M HC1 (200 mL) and add aqueous 2M K.3PO4 to the aqueous phase (~pH 7.5). Extract the aqueous solution with EtOAc (2 x 300 mL), dry over MgS04, filter, and concentrate the filtrate in vacuo to obtain the title compound as pale yellow oil ( 15.5 g, 57% yield). ES/MS (m/z): 352 (M+H).

Preparation 40b

M ethyl 5-[(lR)-l -[trans-4-(3-methoxyazetidin-l-yl)cyclohexyl]ethyl]-4- methylthiophene-3 -carboxylate hydrochloride

o

Methyl 5-[( l R)- l - [trans-4-(3 -methoxyazetidin- 1 -yl)cyclohexyl] ethyl] -4-methyl-thiophene-3-carboxylate hydrochloride may be prepared essentially as described in Preparation 40a, with solvent evaporation of the crude reaction mixture following HCl quenching, and chromatography on silica, eluting with a gradient of 0- 100% 2M

NlVMeOH in DCM, to give oil after solvent evaporation, which partially crystallized upon drying in vacuo. Subsequent recrystallization from EtOAc and a trace of MeOH gives crystalline material sufficient for X-ray crystallography. ES/MS (m/z): 352 (M+H).

Prepare a single crystal of methyl 5-[(lR)-l-[trans-4-(3-methoxyazetidin-l-yl)cyclohexyl]ethyl]-4-methylthiophene-3-carboxylate hydrochloride by recrystallization in EtOAc and MeOH. Mount on a thin fiber at - 173 °C. Collect data using a lu Cu a radiation source (λ = 1 .54178 A) and a Bruker D8 based 3-circle goniometer

diffractometer equipped with a SMART* 6000CCD area detector (crystal dimensions = 0.150 X 0.080 X 0.020 mm). Perform cell refinement and data reduction using the SAINT program V8.32b. Index the unit cell, having monoclinic parameters of 12.2214(3) A, b = 7.0314(2) A, c = 12.8284(3) A, and β = 108.8099( 15)° (cell volume from the crystal structure = 1043.52(5) A3, calculated density of the structure = 1 .235 g/'cm3 at - 173 °C). Determine the structure by direct methods using SHELXS program. Independently define all atomic parameters anisotropically except for the hydrogen atoms. Place at idealized calculated positions. Confirm the space group choice, namely P2\, by successful convergence of the full -matrix least-squares refinement on F2 using the SHELXL program, having a final goodness of fit of 1 .1 10. The Final R indices ( I>2sigma( I)) are Rl = 0.0603, R2 = 0.1242. Refine the absolute structure parameter is to 0.081 ( 12).

Determine the structure. The structure is determined to be the hydrochloride salt and absolute structure is determined to be R- configuration at the stereocenter and transconfiguration around the cyclohexane ring.

Preparation 41

Methyl 2-bromo-5-[(lR)-l-(l,4-dioxaspiro[4.5]decan-8-yl)ethyl]- 4-methyl-thiophene-3 -carboxylate

Add N-bromosuccinimide (6.18 g, 34.7 mmol) to a solution of methyl 5-[(lR)-l-( l ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate ( 15.56 g, 47.97 mmol) in EtOAc (60 mL) and stir the mixture at 55 °C for 30 min, then at 40 °C overnight. Wash the reaction mixture twice with saturated aqueous NaHS03 solution, separate the layers, and dry the combined organic layers over MgS04. Filter and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes, to give the title compound ( 15.67 g, 81 % yield) after solvent evaporation. ES/MS (m/z) (79Br/81Br): 403/405 (M+H).

Preparation 42

Methyl 2-(2- {[(benzyloxy)carbonyl]amino ethyl)-5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5]dec-8- yl)ethyl] -4-methylthiophene-3 -carboxylate

Add methyl 2-bromo-5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5]decan-8-yl)ethyl]-4-methyl-thiophene-3-carboxylate ( 15.44 g, 38.28 mmol), toluene (350 mL) and water (40 mL) into a 1 -L three-neck flask equipped with a mechanical stirrer. Degas the mixture under house vacuum for 15 min. Add potassium benzyl N-[2-(trifluoroboranuidyl)ethyl]carbamate

( 17.3 g, 57.6 mmol), Cs2C03 (37.4 g, 1 15 mmol), and RuPhos-G3-Palladacycle (2.30 g, 2.69 mmol). Degas the mixture for an additional 15 min and then stir under N2 at 80-85 °C overnight. Add saturated aqueous NaHC03 solution and extract three times with EtOAc; wash the combined extracts sequentially with water and saturated aqueous NaCl, dry over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-50% EtOAc in hexanes to afford the title compound ( 14.72 g, 76% yield) as oil. ES/MS (m/z): 502 (M+H).

Preparation 43

2-[( 1 )- 1 -( 1 ,4-Dioxaspiro[4.5]dec-8-yl)ethyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin- 4(5H)-one

Stir a mixture of methyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate ( 14.72 g, 29.35 mmol) and dry 10% Pd on carbon (3.0 g) in MeOH (80 mL) under H2 at 60 psi overnight. Filter the reaction mixture over diatomaceous earth, stir the filtrate at RT for 24 hr and concentrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 20- 100% EtOAc to hexanes and then a gradient of 10% MeOH in EtOAc, to give the title compound (8.20 g, 83% yield) after solvent evaporation. ES/MS (m/z): 336 (M+H).

Preparation 44

3-Methyl-2-[(lR)-l-(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

O

Stir a solution of 2-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (6.18 g, 1 8.4 mmol) in a mixture of TH F (30 mL) and IN HC1 (30 mL) at RT overnight, then at 55 °C for 2 hr. Quench the reaction with solid Na2C03 and extract with EtOAc. Wash the combined extracts with saturated aqueous NaCl and dry over MgS04. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 100 % EtOAc in hexanes, to give the title compound (4.69 g, 87% yield) as foam after solvent removal. ES/MS (m/z): 292 (M+H).

Preparation 45

4-methyl-5-nitrothiophene-3-carboxylate

Add acetic anhydride (2.5 L) to a solution of methyl 4-methylthiophene-3 carboxylate ( 150 g, 0.96 mol) in AcOH (4.5 L) below 25 °C. Cool the mixture to 10 °C, slowly add fuming HN03 (220 mL), keeping the temperature below 15 °C, warm to RT, and stir for 1 hr. Slowly pour the reaction into ice water and extract with EtOAc (2 x 3 L). Separate the resulting layers, sequentially wash the organic phase with water (4 x 3 L) and saturated aqueous NaHC03 solution, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with 5% EtOAc/hexane, to afford the title compound (91 g, 47% yield) as an orange solid after solvent evaporation. Ή NMR (400.1 MHz, DMSO-de) δ 2.77 (s, 3H); 3.83 (s, 3H); 8.61 (s, 1 H).

Preparation 46

Methyl 5-amino-4-methylthiophene-3-carboxylate

o

Add iron ( 166 g, 2.98 mol) slowly to a solution of methyl 4-methyl-5-nitrothiophene-3-carboxylate ( 120 g, 0.55 mol) in AcOH ( 1200 ml .) and EtOH ( 1200 mL). Stir the mixture at 80 °C for 15 min. Cool the reaction, pour slowly into ice water, and add a saturated aqueous solution of NaHC03 until pH 7-7.5. Extract with EtOAc (2 x 3 L), separate the layers, wash the combined organic layers with saturated aqueous NaCl, dry over Na2S04, filter, and evaporate the filtrate in vacuo to obtain the title compound (98 g, 98% yield) as yellow oil, sufficient for use without additional purification. ES/MS (m/z): 172 (M+H).

Preparation 47

Methyl 5 -[(tert-butoxycarbonyl)amino] -4-methylthiophene-3 -carboxylate

To a solution of methyl 5-amino-4-methylthiophene-3-carboxylate (7.79 g, 37.3 mmol) in 1 ,4-dioxane (40 mL), add tert-butoxycarbonyl tert-butyl carbonate ( 16.3 g, 74.6 mmol), heat at reflux for 2 hr, then cool to RT and concentrate the reaction mixture in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 10% EtOAc in hexanes, to afford the title compound (8.88 g, 88% yield) as thick yellow oil after solvent evaporation. ES/MS (m/z): 272 (M+H).

[Reparation 48

Methyl 5-[ 1 ,4-dioxaspiro[4.5]dec-8-yl(methyl)amino]-4-methylthiophene-3-carboxylate

To a solution of methyl 5 -[(tert-butoxycarbonyl )amino] -4-methylthiophene-3 -carboxylate (2.01 g, 7.41 mmol) in DMF (20 mL) add Cs2C03 (6.03 g, 18.5 mmol) and

CH3I ( 1.05 g, 7.41 mmol). Heat the mixture at 80 °C for 10 min and cool the reaction mixture to RT. Dilute with DCM (50 mL) and water ( 10 mL), separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Add MeOH (40 mL) and 5M aqueous HCl (20 mL) to the resulting residue, and heat at 50 °C for approximately 1 hr. Concentrate the mixture in vacuo, dilute with DCM and add solid NaHC03 until the mixture is neutralized to about pH 7. Separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo to give crude methyl 4-methyl-5-(methylamino)-thiophene-3-carboxylate. ES/MS (m/z): 1 86 (M+H).

Dissolve the crude methyl 4-methyl -5 -(methylamino)-thiophene-3 -carboxylate in DCM (20 mL), add l,4-dioxaspiro[4.5]decan-8-one ( 1 .16 g, 7.40 mmol) while stirring for 30 min, then add sodium triacetoxyborohydride (3.13 g, 14.8 mmol) and stir at RT for an additional 30 min. Add additional l,4-dioxaspiro[4.5]decan-8-one (0.289 g, 1 .85 mmol), stir for 15 min, add more sodium triacetoxyborohydride (0.784 g, 3.70 mmol), and stir the resulting mixture overnight at RT. Dilute the reaction with saturated aqueous NaHC03 solution ( 10 mL) and DCM (40 mL), stir for 1 hr, separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 10% EtOAc in hexanes, to afford the title compound ( 1.21 g, 50% yield) as colorless oil after solvent evaporation. ES/MS (m/z): 326 (M+H).

Preparation 49

Methyl 2-bromo-5-[l,4-dioxaspiro[4.5]dec-8-yl(methyl)

methylthiophene-3-carboxylate

To methyl 5 - [ 1 ,4-dioxaspiro [4.5] dec- 8-yl(methyl)amino] -4-methylthiophene-3 -carboxylate (1.13 g, 3.47 mmol) in DCM ( 1 1 mL) add N-bromosuccinimide (0.701 g, 3.82 mmol) at RT. After 5 min, dilute the reaction with DCM (40 mL) and wash with O.lMNaOH (2 x 10 mL). Separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo to afford the crude title compound ( 1.47 g, quantitative yield) as brown oil. ES/MS (m/z): ( 'ΈΓΓ ΒΓ) 404/406 (M+H).

Preparation 50

Methyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-[l,4-dioxaspiro[4.5]dec-8- yl (methyl)amino] -4-methylthiophene-3 -carboxylate

Add toluene ( 15 ml.) and water (2.5 mL) to crude methyl 2-bromo-5-[ l ,4-dioxaspiro[4.5]dec-8-yl(methyl)amino]-4-methylthiophene-3-carboxylate ( 1 .36 g, 3.20 mmol), potassium benzyl N-[2-(trifluoroboranuidyl)ethyl]carbamate ( 1.25 g, 4.15 mmol) and CS2CO3 (3.64 g, 1 1 .2 mmol) in a flask. Purge the mixture with N2, then add RuPhos (0.0761 g, 0.160 mmol) and 2nd generation Ruphos precatalyst (0.124 g, 0. 160 mmol). Stir the mixture vigorously and heat at 100 °C for 18 hr. Cool to RT and dilute the reaction with EtOAc (40 mL) and water ( 10 mL). Separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-30% EtOAc in hexanes, to afford the title compound (0.93 g, 58% yield) as orange oil after solvent evaporation. ES/MS (m/z): 503 (M+H).

Preparation 51

2-[l,4-Dioxaspiro[4.5]dec-8-yl(methyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin- 4(5H)-one

To methyl 2-(2-{[(benzyloxy)carbonyl]amino ethyl)-5-[ l ,4-dioxaspiro[4.5]dec-8-yl(methyl)amino]-4-methylthiophene-3 -carboxylate (0.93 g, 1.86 mmol) in MeOH ( 10 mL), add 20% Pd(OH)2 on carbon (0.500 g, 3.56 mmol) and TEA (0.78 mL, 5.57 mmol). Charge the reaction vessel with H2 (345 kPa) and stir at RT. After about 1 .5 hr remove the catalyst by filtration, then heat the mixture at 70 °C for 5 hr. Cool the mixture to RT and concentrate in vacuo to afford the title compound (0.5 13 g, 82% yield) as yellow foam, sufficient for use without additional purification. ES/MS (m/z): 337 (M+H).

Preparation 52

Methyl 5-[ {trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl} (ethyl)amino]-4- methylthiophene-3-carboxylate

Add sodium triacetoxyborohydride (441 g, 2.05 mol) to a solution of methyl 5-amino-4-methylthiophene-3-carboxylate (98 g, 0.57 mol) in DCE (1000 mL) containing tert-butyl (4-oxocyclohexyl)carbamate ( 156.7 g, 0.75 mol) and AcOH ( 1 1 8 mL) at RT. Stir the resulting mixture for 30 min at RT, add acetaldehyde (63.7 mL, 1.15 mol), stir for another 45 min, and add water followed by saturated aqueous NaHC03 solution (pH ~9-10). Extract the aqueous mixture with EtOAc (2 x 3 L), wash combined organic extracts with saturated aqueous NaCl, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with 5% EtOAc in hexanes, to give 337 g of cis-/trans- mixture after solvent removal. Separate the cis-and trans- isomers by multiple sequential chiral SFC runs (CH IRALPAK* AD, 5 μιη, 5 x 25 cm; eluent: isocratic mixture of 5% MeOH in C02; Column Temp: 50 °C; Flow Rate: 400 g/min) to afford the pure trans- title compound ( 1 83 g, 76% yield) as a brown solid after solvent removal. Rt = 3.54 min. ES/MS (m/z): 397 (M+H).

Preparation 53

Methyl 5-[(trans-4-aminocyclohexyl)(ethyl)amino]-4-methylthiophene-3-carboxylate

H N

Cool a solution of methyl 5-[[4-(tert-butoxycarbonylamino)cyclohexyl]-ethyl-amino]-4-methyl-thiophene-3-carboxylate (40 g, 100.9 mmol) in THF (200 mL) to 0 °C. Add a solution of 4 HC1 in dioxane (250 mL, 1000 mmol) drop wise, and stir the resulting mixture at RT for 16 hr. Concentrate in vacuo to - 1/4 volume, add EtOAc (400 mL) and saturated aqueous K2CO3 solution (200 mL), and stir the resulting mixture at RT for 1 hr. Separate the resulting phases, wash aqueous phase with EtOAc (2 x 100 mL), combine the organic layers, and wash sequentially with water (100 mL) and saturated aqueous NaCl ( 100 mL). Dry the organic layer over Na2S04, filter, and concentrate the filtrate in vacuo to give the title compound (31 .7 g, quantitative yield) as dark brown oil after solvent evaporation. ES/MS (m/z): 297 (M+H).

Preparation 54

2-Methoxypropane- 1 ,3-diol

To a cold solution of dimethyl 2-methoxypropanedioate (25 g, 154.19 mmol) in THF (300 mL) at - 15 °C, add a solution of 2.3M LAH in 2-methyltetrahydrofuran ( 170 mL, 150 g, 385.47 mmol) drop wise at - 15 °C and stir for 2 hr at 0 °C, then for 1 hr at RT. Re-cool to - 15 °C and slowly quench with water ( 15 mL), 2N KOH ( 15 mL) and water (30 mL), and stir the resulting mixture for 30 min at RT. Filter the resulting white solids, wash solids with EtOAc (250 mL) followed by 40% (v/v) MeOH/EtOAc (500 mL), and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica gel, eluting with a gradient of 0-20% MeOH in EtOAc, to afford the title compound as colorless oil (6.66 g, 40% yield) after solvent evaporation. Ή NMR (400. 1 MHz, CDCI3) δ 2.50 (bs, 2H), 3.47 (s, 3H), 3.36 (quintet, J= 4.5 Hz, 1 H), 3.69 (dd, J= 4.6, 1 1 .7 Hz, 2H), 3.79 (dd, J= 4.2, 1 1.7 Hz, 2H).

Preparation 55

Methyl 5- {ethyl [trans-4-(3-methoxyazetidin-l -yl)cyclohexyl]amino} -4-methylthiophene- 3-carboxylate

Drop wise add tritluoromethanesulfonic anhydride (36.47 mL, 61.16 g, 214.6 mmol) to a solution of 2-methoxypropane- 1 ,3-diol (14.81 g, 139.6 mmol) in ACN (500 mL) at -20 °C over 45 min. Then add drop wise DIPEA (44.4 mL, 32.9 g, 255 mmol) over 35 min and stir the resulting mixture for 45 min at - 15 °C. Cool the mixture to -25 °C and add DIPEA (44.4 mL, 32.9 g, 255 mmol) drop wise over 20 min. Add a solution of methyl 5-[(trans-4-aminocyclohexyl)(ethyl)amino]-4-methylthiophene-3-carboxylate 31 .72 g, 107.0 mmol) in ACN (300 mL) drop wise over 30 min. Warm the reaction to RT and then stir at 70 °C for an additional 1 hr. Cool the mixture to RT, dilute with EtOAc (500 mL) and water (500 mL), separate phases, and extract the aqueous phase with EtOAc (2 x 250 mL). Add a solution of 4M aqueous K2CO3 (250 mL) to the combined organic extracts and stir for 2 hr at RT. Separate phases, wash the organic layer with saturated aqueous NaCl (250 mL), dry organic layer over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 10% MeOH in EtOAc, to afford the title compound (29.2 g, 74% yield) as a brown solid after solvent evaporation. ES/MS (m/z): 367 (M+H).

Preparation 56

Methyl 2-bromo-5-{ethyl[trans-4-(3-methoxyazetidin-l-yl)cyclohexyl]amino}-4- methylthiophene-3-carboxylate

Mix methyl 5 - {ethyl [trans-4-(3 -methoxyazetidin- 1 -yl)cyclohexyl] amino } -4-methylthiophene-3-carboxylate (29.17 g, 79.59 mmol) and NBS ( 17.00 g, 95.51 mmol) in DMF (400 mL) and stir the resulting mixture for 2 hr at RT. Dilute with EtOAc (400 mL) and water (250 mL), separate the phases, and wash the organic layer sequentially with AM aqueous K2CO3 solution (2 x 200 mL), water (200 mL), and saturated aqueous NaCl (200 mL). Dry the organic layer over Na2S04, filter, and concentrate the filtrate in vacuo to give the title compound (32.4 g, 89% yield) as brown oil, suitable for use in the next step without further purification. ES/MS (m/z) (79Br/81Br): 445, 447 (M+H).

Preparation 57

Methyl 2-(2- {[(benzyloxy)carbonyljamino } ethyl )-5 - {ethyl [trans-4-(3 -methoxyazetidin- 1 - yl)cyclohexyl]amino}-4-methylthiophene-3-carboxylate o

To a solution of K2C03 (657.8 g, 414.3 mmol) in water ( 123 mL, 6828 mmol) add potassium benzyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (23.62 g, 82.85 mmol) drop wise followed by a solution of methyl 2-bromo-5-{ethyl[trans-4-(3-methoxyazetidin-l -yl)cyclohexyl] amino }-4-methylthiophene-3-carboxylate (32.37 g, 69.04 mmol) in toluene (450 mL). Purge the mixture gently with N2 while warming to 90 °C over 30 min, then add 2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl (2.46 g, 5.1 8 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l , I '-biphenyl)[2-(2'-amino- 1 .1 '-biphenyl)]palladium (II) (4.02 g, 5.18 mmol). Stir the resulting mixture at 105 °C for 4

hr, cool to RT, dilute with EtOAc (300 mL) and water ( 100 mL), separate the phases, extract the aqueous phase with EtOAc (3 x 100 mL), and wash the combined organic layers sequentially with AM aqueous K2C03 (2 x 100 mL), water ( 150 mL), and saturated aqueous NaCl ( 150 mL). Dry the organic layer over Na2S04, concentrate the filtrate in vacuo, and subject the resulting residue to chromatography on silica, eluting with a gradient of 0-5% MeOH in EtOAc, to afford the title compound (23.1 g, 51 % yield) as brown oil after solvent evaporation. ES/MS (m/z): 544 (M+H).

Preparation 58

Methyl 5-{ethyl[trans-4-(3-methoxyazetidin- 1 -yl)cyclohexyl] amino} -2-(2- { [(2-methoxy- 4,6-dimethylpyridin-3-yl)methyl]amino}ethyl)-4-methylthiophene-3-carboxylate

o

Add Pd(OH)2 on carbon, 20% dry basis, water wet (5.75 g) to a mixture of methyl 2-(2- { [(benzyloxy)carbonyljamino } ethyl )-5 - {ethyl [trans-4-(3 -methoxyazetidin- 1 -yl)cyclohexyl]amino}-4-methylthiophene-3-carboxylate (23.00 g, 35.1 1 mmol) and 2-methoxy-4,6-dimethyl-pyridine-3-carbaldehyde (7.03 g, 42.13 mmol) in EtOH (280 mL) and stir at 50 °C under H2 (70 psi) for 24 hr. Filter the mixture through diatomaceous earth, rinse with EtOH, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-25% MeOH in DCM, to afford the title compound ( 18.4 g, 89% yield) as brown oil after solvent evaporation. ES/MS (m/z): 559 (M+H).

Preparation 59

2- {Ethyl[trans-4-(3-methoxyazetidin-l -yl)cyclohexyl] amino} -5-[(2-methoxy-4,6- dimethylpyridin-3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

o

Stir a mixture of methyl 5- {ethyl [trans-4-(3-methoxyazetidin- 1 -yl)cyclohexyl]amino}-2-(2-{[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]amino}ethyl)-4-methylthiophene-3-carboxylate (18.35 g, 30.2 1 mmol) and AcOH (9.07 g, 1 5 1 . 1 mmol) in toluene ( 175 mL) at 1 10 °C for 3 hr. Cool the mixture, dilute with EtOAc (250 mL) and water ( 1 50 mL), separate phases, extract the aqueous phase with EtOAc (3 x 1 00 mL), wash the combined organic extracts sequentially with AM aqueous K2C03 solution (2 X 100 mL), water ( 150 mL), and saturated aqueous NaCl ( 1 50 mL). Dry the organic layer over Na2S04, filter, and concentrate the filtrate in vacuo, to afford the title compound ( 16.42 g, 95% yield) as brown oil suitable for use without additional purification. ES/MS (m/z): 527 (M+H).

Preparation 60

Methyl 5-[ l ,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-4-methylthiophene-3-carboxylate

To a solution of methyl 5-amino-4-methylthiophene-3-carboxylate (43 g, 25 1 mmol), 1 ,4-dioxaspiro[4.5]decan-8-one (39.23 g, 25 1 mmol) and AcOH (47 mL) in DCE (430 mL) slowly add sodium triacetoxyborohydride ( 159.6 g, 754 mmol) below 25 °C. Stir the mixture at RT for 30 min and then add acetaldehyde (28 mL, 503 mmol). Stir the mixture at RT for 30 min. Pour the contents of the mixture into ice water and basi fy by addition of a saturated aqueous NaHC03 solution until pH 7.0-7.5. Extract the resulting mixture with EtOAc (2 x 3 L), wash with saturated aqueous NaCl , dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to

chromatography on silica, eluting with 5% EtOAc in hexanes, to afford the title compound (55 g, 67% yield) as a solid after solvent evaporation. ES/MS (m/z): 340 (M+H).

Preparation 61

Methyl 2-bromo-5-[ l ,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-4-methylthiophene-3- carboxylate

To a three-neck round bottom flask equipped with an addition funnel, add a solution of methyl 5-[l,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-4-methylthiophene-3-carboxylate (91 g, 268.1 mmol) in DCM ( 1 .2 L). Cool the flask to 0 °C, then add NBS (58.4 g, 322 mmol) portion-wise over 1 hr. Remove the ice bath and stir the reaction mixture at RT for 2 hr. Add water, separate the organic layer and concentrate the organic phase in vacuo. Subject the resulting residue to chromatography on silica in four batches, eluting each with 10-50% EtOAc in hexanes. Concentrate the combined fractions from the first two batches to afford oil. Dry the material in vacuo overnight to afford a white solid (40.9 g). Concentrate fractions from batches three and four to afford brown oil. Treat the resulting material with a small amount of hexanes until a solid appears, filter, and dry in vacuo overnight to afford a light brown solid (37.9 g). Combine the two resulting collected batches to afford the title compound (78.8 g, 70% yield) as brown oily solid. ES/MS (m/z): (79Br/81Br) 418/420 (M+H).

Preparation 62

Methyl 2-bromo-5-[ethyl(4-oxocyclohexyl)amino]-4-methylthiophene-3-carboxylate

To methyl 2-bromo-5-[l ,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-4-methylthiophene-3-carboxylate (7.81 g, 18.7 mmol) in TH F ( 140 mL) add 1 M aqueous HC1 ( 100 mL). Stir the reaction at RT for about 25 hr. Dilute the reaction mixture with EtOAc (200 mL) and separate the layers. Wash the organic layer with saturated aqueous NaHC03 (2 X 25 mL). Dry the organic layer over Na2S04, filter, and concentrate the filtrate in vacuo to afford the crude title compound (6.7 1 g, 96% yield) as reddish brown thick oil, sufficient for use in the next step without additional purification. ES/MS (m/z): (79Br/81Br) 374/376 (M+H).

Preparation 63

Methyl 2-(2- { [(benzyloxy)carbonyl]amino } ethyl)-5-[ l ,4-dioxaspiro[4.5]dec-8- yl(ethyl)amino]-4-methylthiophene-3-carboxylate

In two separate batches, add toluene (428 mL) and water ( 100 mL) to a mixture of methyl 2-bromo-5-[ l ,4-dioxaspiro[4.5]dec-8-yl(ethy )amino]-4-methylthiophene-3-carboxylate (20 g, 48 mmol), potassium benzyl N-[2- (trifluoroboranuidyl)ethyl]carbamate ( 17.5 g, 58.9 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II)

methanesul fonate (4. 1 g, 4.8 mmol) and Cs2C03 (47 g, 144 mmol). Flush the reaction mixture with N2, then heat at 80 °C for 4 hr. Pour the reaction mixture into ice-cold water, add EtOAc, separate the layers, filter the organic phase over diatomaceous earth, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 5-40% EtOAc in hexanes Concentrate the resulting desired fractions and dry in vacuo for 72 hr to afford the title compound (41 .9 g combined mass, 85% combined yield from two runs) as brown oil. ES/MS (m/z): 5 17 (M+H).

Preparation 64

2-[l,4-Dioxaspiro[4.5]dec-8-yl(ethyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin- 4(5H)-one

Purge a Parr flask with N2, add 20% Pd(OH)2 on carbon (40 g, 284.9 mmol), purge the flask with N2 again, and add TEA ( 150 mL, 1080 mmol), MeOH (500 mL) and a solution of methyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-[l,4-dioxaspiro[4.5]dec-8-yl(ethyl )amino] -4-methylthiophene-3 -carboxylate (39.5 g, 76.5 mmol) in MeOH (500 mL). Seal the flask, purge with N2, purge with H2 gas, and fill the system with H2 (414 kPa). Stir for about 4 hr at RT and allow the reaction mixture to sit for 72 hr. Filter the resulting suspension, concentrate the filtrate in vacuo, dissolve the resulting residue in EtOAc, and add a little Et20 until a solid forms. Filter and collect the resulting solid to give the title compound ( 15.3 g) as a white solid. Concentrate the yellow filtrate and subject the resulting residue to chromatography on silica, eluting with a gradient of 10-60% EtOAc in hexanes, to afford additional title compound (8 g). Combine filtered and chromatographed material for further use (23.3 g, 86% yield). ES/MS (m/z): 351 (M+H).

Preparation 65

tert-Butyl 4-{ethyl[4-(methoxycarbonyl)-3-methylthiophen-2-yl]amino}piperidine-l- carboxylate

To a round bottom flask, add methyl 5-amino-4-methylthiophene-3-carboxylate (-50% purity, 34 g, 99 mmol), tert-butyl-4-oxopiperidine- 1 -carboxylate (25.7 g, 129 mmol) in DCE (408 mL) and AcOH ( 17 mL, 297 mmol), stir at RT for 10 min, then cool to 0 °C and slowly add sodium triacetoxyborohydride (54.2 g, 248 mmol) portion-wise.

Gradually warm the reaction mixture to RT and stir for 2 hr. Add acetaldehyde ( 1 1 . 1 mL, 1 99 mmol) drop wise, then stir for 72 hr. Cool the reaction mixture to 0 °C, quench with saturated aqueous NaHCCb solution, and dilute with DCM. Separate the layers, extract the aqueous layer with DCM, combine the organic phases, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 10% EtOAc in hexanes, to afford the title compound (6.4 g, 17% yield) as an orange solid after solvent evaporation. ES/ S (m/z): 383 (M+H).

Preparation 66

tert- Butyl 4- { [5-bromo-4-(methoxycarbonyl)-3-methylthiophen-2- yl] (ethyl)amino } piperidine- 1 -carboxylate

To a round bottom flask, add tert-butyl 4- {ethyl [4-(methoxycarbonyl)-3-methylthiophen-2-yl]amino piperidine- 1 -carboxylate (6.4 g, 1 7 mmol) in DCM (84 mL), cool to 0 °C, add NBS (3.3 g, 1 8 mmol) portion-wise, and stir for 1 hr. Dilute the reaction mixture with water, separate the layers, extract the aqueous layer with additional DCM, combine the organic phases, dry over Na2S04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes, to afford the title compound (6.7 g, 87% yield) as orange oil after solvent removal. ES/MS (m/z): (79Br/81Br) 405/407 (M+H - t-butyl).

Preparation 67

tert-Butyl 4- { [5 -(2- { [(benzyloxy)carbonyl]amino } ethyl)-4-(methoxycarbonyl)-3- methylthiophen-2-yl] (ethyl)amino piperidine- 1 -carboxylate

In two separate batches, add tert-butyl 4- { [5-bromo-4-(methoxycarbonyl)-3-methylthiophen-2-yl](ethyl)amino } piperidine- 1 -carboxylate (0.900 g, 1 .95 mmol), potassium benzyl N-[2-(trifluoroboranuidyl)ethyl]carbamate (0.695 g, 2.34 mmol), (2-dicyclohexyl-phosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl)[2-(2'-amino-l , 1 '-biphenyl)]palladium(ll) methanesulfonate (0. 167 g, 0.195 mmol), Cs2C03 ( 1 .91 g, 5.85 mmol), toluene (9.75 mL) and water (3.55 mL) to a round bottom flask. Degas each mixture with N2 for 15 min, then heat at 90 °C overnight. Cool each reaction mixture to RT and combine. Quench with ice water, dilute with EtOAc, separate the layers, extract the aqueous layer with additional EtOAc, combine the organic phases, and dry over Na2S04. Filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-30% EtOAc in hexanes, to afford the title compound ( 1.29 g, 59% yield) as yellow oil after solvent evaporation. ES/MS (m/z): 460 (M+H- BOC).

Preparation 68

tert- Butyl 4-[ethyl(3-methyl-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2- yl)amino]piperidine- 1 -carboxylate

To a round bottom flask, add tert-butyl 4- {[5-(2- {[(benzyloxy)carbonyl]amino}ethyl)-4-(methoxycarbonyl)-3-methylthiophen-2-yl](ethyl)amino piperidine- 1 -carboxylate ( 1.29 g, 2.30 mmol) in MeOH (23 mL) and THF (15 mL), degas with N2 for -10 min, add 10% Pd on carbon ( 1.29 g) and TEA (0.400 mL, 2.84 mmol), then place under an atmosphere of H2 and stir at RT for about 72 hr. Filter the reaction mixture through diatomaceous earth, wash with MeOH, and concentrate the filtrate in vacuo. Transfer the residue to a microwave vial, add TEA (0.300 mL), and heat at 90 °C for 2 hr. Cool to RT with stirring overnight, then concentrate the reaction mixture in vacuo. Subject the resulting residue to

chromatography on silica, eluting with a gradient of 0-30% ACN in DCM, to afford the title compound (0.466 g, 5 1 % yield) as yellow foam after solvent evaporation. ES/MS (m/z): 394 (M+H).

Preparation 69

Methyl 2-(3- {[(benzyloxy)carbonyl] -amino } prop- 1 -yn- 1 -yl)-5 -[( 1 R)- 1 -( 1 ,4- dioxaspiro[4.5]dec-8-yl)ethyl]-4-methyl-thiophene-3-carboxylate

To a mixture of crude methyl 2-bromo-5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5jdecan-8-yl )ethyl j -4-methyl-thiophene-3 -carboxy ate ( 10.1 g, 25.0 mmol), Cul ( 1 .91 g, 10.0 mmol), and benzyl prop-2-yn- 1 -ylcarbamate ( 1 1.4 g, 60.3 mmol) in 1 ,4-dioxane ( 130 mL) add TEA (52 mL, 369 mmol). Degas and purge the mixture with N2, then add bis(triphenylphosphine)palladium(II) dichloride (3.6 g, 5.1 mmol). Stir at 40 °C for 1 hr. Filter the mixture over diatomaceous earth and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-20% EtOAc in hexanes, to afford the title compound ( 10.8 g, 80% yield) as light brown oil after solvent evaporation. ES/MS (m/z): 5 12 (M+H).

Preparation 70

Methyl 2-(3-aminopropyl)-5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4- methylthiophene-3 -carboxylate

Add TEA (0.500 mL, 3.55 mmol) to a mixture of methyl 2-(3-{[(benzyloxy)carbonyl]-amino}prop-l-yn-l-yl)-5-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methyl-thiophene-3 -carboxylate ( 10 g, 19.55 mmol) in MeOH ( 150 mL). Degas and purge the mixture with N2, add 20% Pd(OH)2 on carbon (4.10 g, 5.84 mmol), charge the reaction vessel with H2 (414 kPa) and stir overnight. Add an additional portion of 20% Pd(OH)2 on carbon (500 mg, 0.712 mmol) and TEA (0.500 mL, 3.55 mmol), degas with N2 again and charge the reaction vessel with H2 (414 kPa). Stir for an additional 6 hr, filter the reaction over diatomaceous earth, and concentrate the filtrate in vacuo to yellow oil. Subject the resulting oil to chromatography on silica, eluting with a gradient of 0-30% MeOH in DCM, to afford the title compound (6.6 g, 89% yield) as yellow oil after solvent evaporation. ES/MS (m/z): 382 (M+H).

Preparation 71

2-[(lR)-l-(l,4-Dioxaspiro[4.5]dec-8-yl)ethyl]-3-methyl-5,6,7,8-tetrahydro-4H- thieno[3,2-c]azepin-4-one

To a microwave vial, add a solution of methyl 2-(3-aminopropyl)-5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate ( 1.5 g, 3.9 mmol) in toluene (8 mL), then add KOtBu (940 mg, 7.87 mmol). Stir the mixture at 90 °C overnight. Pour the reaction into ice-cold saturated aqueous NaHC03 solution, extract with DCM, separate the layers, and concentrate the organic layer in vacuo. Subject the

resulting residue to chromatography on silica, eluting with a gradient of 0-5% MeOH in DCM, to afford the title compound (1.3 g, 85% yield) as a light brown solid after solvent evaporation. ES/MS (m/z): 350 (M+H).

Preparation 72

2-[( 1 )- 1 -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-5-[(2-methoxy-4,6-dimethylpyridin-3- yl)methyl]-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one

To a solution of 2-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one ( 1.1 g, 3.1 mmol) in THF ( 10 mL) add ground KOH (700 mg, 12.4 mmol). Stir for 30 min, then add 3-(chloromethyl)-2-methoxy-4,6-dimethyl-pyridine (700 mg, 3.77 mmol) dissolved in THF ( 1 mL), and stir the resulting mixture for 2 hr. Pour the reaction mixture into ice-cold saturated aqueous NaHC03 solution, extract with DCM, separate the layers, and concentrate the organic layer in vacuo. Dry the resulting residue under vacuum to afford the crude title compound (2.2 g, 87% yield) as brown oil, suitable for additional use without additional purification. ES/MS (m/z): 499 (M+H).

Preparation 73

5 -[(4,6-Dimethyl-2-oxo- 1 ,2-dihydropyridin-3 -yl)methyl] -3 -methyl-2- [(1 R)- 1 -(4- oxocyclohexyl)eth -5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one

Add PTSA ( 1 .3 g, 7.2 mmol) to crude 2-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl] -5 - [(2-methoxy-4,6-dimethylpyridin-3 -yl)methyl]-3-methyl-5 ,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one ( 1 .0 g, 1.2 mmol) in DMF ( 10 mL), and stir the resulting mixture at 70 °C for 2 hr. Pour the mixture into ice-cold saturated aqueous NaHC03 solution, extract with DCM, separate the layers, and concentrate the organic layer in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-5% MeOH in DCM, to afford the title compound (680 mg, quantitative yield) as light brown oil after solvent evaporation. ES/MS (m/z): 441 (M+H).

Preparation 74

2-[(lR)-l-{Trans-4-[3-(cyclopropoxy)azetidin-l-yl]cyclohexyl}ethyl]-3-methyl-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one

Add titanium(IV) isopropoxide ( 1.40 g, 4.9 mmol) and 3-(cyclopropyloxy)azetidine hydrochloride (0.74 g, 4.9 mmol) to a solution of 3-methyl-2-[(lR)-l-(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.72 g, 2.5 mmol) in DCM ( 10 mL) containing DIPEA (0.87 mL, 4.9 mmol), stir the resulting reaction mixture at RT for 1 8 hr, and concentrate the reaction mixture in vacuo. Add

THF (4 mL) and MeOH (6 mL) to the remaining residue and cool the resulting solution to -78 °C. Add 2M L1 BH4 in THF ( 1.9 mL, 3.8 mmol) drop wise and gradually warm to RT over 3 hr. Dilute the reaction mixture with a 1 : 1 mixture of DCM/CHCI3 ( 100 mL) and 50% saturated NaHC03 solution (50 mL), separate the resulting layers, dry the combined organic extracts over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 10-50% of a mixture of 10% MeOH in DCM and DCM to give the title compound (0.40 g, 42% yield) after solvent evaporation. ES/MS (m/z): 389 (M+H).

Prepare the following compounds essentially by the method of Preparation 74 using the corresponding substituted azetidine.

3-Methyl-2-[(lR)-l -(trans- 4-{3-[(3R)- tetrah ydro furan- 3 - 80 yloxyjazetidin- 1 - 419

yl } cyclohexyl)ethyl] -6,7- dihydrothieno[3,2- c]pyridin-4(5H)-one

Preparation 81

2-[(lR)-l-{Trans-4-[3-(methoxymethyl)azetidin-l-yl]cyclohexyl}ethyl]-3-methyl-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one

Stir a mixture of 3-(methoxymethyl)azetidine hydrochloride (368 mg, 2.67 mmol) and DIPEA (400 mg, 3.06 mmol) in MeOH (5 mL) under N2 at RT for 10 min, add 3- methyl-2-[(lR)-l-(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (400 mg, 1.37 mmol), and stir the mixture for 4 hr. Cool to -78 °C, slowly add 2M LiBH4 in THF (0.90 mL, 1 .8 mmol), and gradually warm up to RT overnight. Concentrate the mixture in vacuo, dilute the resulting residue with saturated aqueous NaHC03 solution, extract with DCM, and separate the resulting layers. Dry the organic layer over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to

chromatography on silica, eluting with a gradient of 0-80% of a mixture of ( 10% 2NNH3 MeOH solution) in DCM and DCM. Combine the fractions containing the desired product and concentrate in vacuo. Subject the resulting residue to reverse-phase chromatography over C- 18-silica (40 g), eluting with 10 mM NH4HC03, pH 10, in 5% MeOH/water and ACN using a step gradient of 100% 10 mM N H4HCO3 in 5%

MeOH/water for 5 min, then 25% ACN/10 mM NH4HCO3 in 5% MeOH/water for 5 min, then a linear gradient of 25%-9()% ACN/10 mM N H4HCO3 in 5% MeOH/water.

Combine the pure fractions and concentrate in vacuo to give the title compound ( 1 14 mg, 22% yield). ES/MS (m/z): 377 (M+H).

Preparation 82

5 - { [2-(Benzyloxy)-4,6-dimethylpyridin-3-yl]methyl }-2-[( l R)- l - {trans-4- [3 - (cyclopropyloxy)azetidin- 1 -yljcyclohexyl } ethyl] -3 -methyl-6,7-dihydrothieno[3 ,2- c]pyridin-4(5H)-one

Slowly add 0.7A H DS in toluene ( 1.2 mL, 0.84 mmol) to a solution of 2-[( 1 )- 1 - (trans-4-[3-(cyclopropoxy)azetidin- 1 -yljcyclohexyl } ethyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (230 mg, 0.59 mmol) in THF ( 10 mL) at RT over 30 min, and stir an additional 30 min. Drop wise add a solution 2-benzyloxy-3- (chloromethyl)-4,6-dimethyl-pyridine (200 mg, 0.76 mmol) in THF (5 mL) and stir at RT for 1 8 hr. Heat the reaction mixture to 55 °C, stir for 1 hr, cool to RT, pour into an ice-cold aqueous aHCOj solution, and extract with EtOAc. Separate the layers, wash the organic extract with saturated aqueous NaCl, dry over MgS04, filter, and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient 10-50% EtOAc in hexanes, to yield the title compound (210 mg, 57% yield) after solvent evaporation. ES/MS (m/z): 614 (M+H).

Prepare the following compounds essentially by the method of Preparation 82 and the appropriately substituted 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one.

5- {[2-(Benzyloxy)-4,6- dimethylpyridin-3- yl]methyl}-3-methyl-2- [(lR)-l-{trans-4-[3-(lH- b O

87 624

pyrazol- 1 -yl)azetidin- 1 - yl]cyclohexyl}ethyl]-6,7- dihydrothieno[3,2- c]pyridin-4(5 H )-one

5-{[2-(Benzyloxy)-4,6- dimethylpyridin-3- yl]methyl}-3-methyl-2- [(lR)-l-(trans-4- {3-[(3S)- b O

88 tetrahydrofuran-3- 644

yloxyjazetidin- 1 - yl}cyclohexyl)ethyl]-6,7- dihydrothieno[3,2- c]pyridin-4(5H)-one

5- { [2-(Benzyloxy)-4,6- dimethylpyridin-3- yl]methyl}-3-methyl-2- [( l R)- l -(trans-4- {3-[(3R)- & O

89 tetrahydrofuran-3- 644

yloxyjazetidin- 1 - yl}cyclohexyl)ethyl]-6,7- dihydrothieno[3,2- c]pyridin-4(5H)-one

Preparation 90

Methyl 5-[( 1 R)- 1 -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-2-(2- {[(2-methoxy-4,6- dimethylpyridin-3-yl)methyl]amino}ethyl)-4-methylthiophene-3-carboxylate

Dissolve methyl 2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-5-[(lR)-l-(l,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-methylthiophene-3-carboxylate (77 g, 153.5 mmol) and 2-methoxy-4,6-dimethyl-pyridine-3-carbaldehyde (23.3 g, 140 mmol) in EtOH (500 mL) in a Parr reactor and add Pd(OH)2 on carbon, 20% dry basis, water wet ( 1 1.5 g). Fill the vessel with H2 ( 100 psi) and stir for 3.5 hr at 50 °C. After cooling to RT, filter the mixture through diatomaceous earth and wash with EtOH. Concentrate the filtrate in vacuo, add toluene (800 mL) to the residue, and continue partial distillation of volatiles to a final weight of approximately 400 g, to obtain the title compound as a solution in toluene, suitable for use in the next step without additional purification. ES/MS of an evaporated sample (m/z): 517 (M+H).

Preparation 91

Methyl 2-(2- { [(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]amino} ethyl)

[( 1 R)-l -(4-oxocyclohexyl)ethyl]thiophene-3-carboxylate o

To the crude toluene solution (approximately 76 g) of methyl 5-[( l R)- l -( 1 ,4-dioxaspiro[4.5]dec-8-yl)ethyl]-2-(2-{[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]amino}ethyl)-4-methylthiophene-3-carboxylate, from preparation 90, add 1 M aqueous HCl (800 mL) and stir at RT for 1 hr. Separate the layers, wash the organic layer sequentially with 2M aqueous HCl (2 x 50 mL), and wash combined acidic aqueous layers with toluene ( 100 mL). Add toluene (0.4 L) to the aqueous layer and add 6M aqueous K2CO3 to pH 9, stir for 5 min, separate the phases, wash the organic layer with aqueous saturated NaCl, then pass through a short pad of Na2S04. Further rinse Na2S04 pad with toluene to obtain a crude toluene solution of the title compound (approximate volume 1 L), suitable for use in the next step without additional purification. ES/MS of an evaporated sample (m/z): 473 (M+H).

Preparation 92

5-[(2-Methoxy-4,6-dimethy]pyridin-3 -yl)methyl]-3-methy -2-[( 1 R)- l -(4- oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

O

Add AcOH (9 mL, 1 57. 1 mmol) to the crude solution of methyl 2-(2-{[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]amino } ethyl )-4-methy 1-5 - [( 1 R)- 1 -(4-oxocyclohexyl)ethyljthiophene-3-carboxylate ( 1 L, approximately 79 g, from preparation 91 ) and stir at 90 °C for 2 hr. Wash the mixture twice with 2M aqueous HCl (total 0. 15 L), and sequentially once each with water, 1 M aqueous K3PO4, and saturated aqueous NaCl (each 0. 1 L). Dry the organic layer over MgS04, filter, and evaporate the filtrate in vacuo to afford the title compound as orange viscous oil (40.98 g, 48.5% yield). ES/MS (m/z): 441 (M+H).

[Reparation 93

5- [(2-Methoxy-4,6-dimethylpyridin-3-yl)methyl] -2- {( 1 R)- 1 - [trans-4-(3 -methoxyazetidin- 1 -yl)cyclohexyl] ethyl} -3 -methyl -6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

Add DIPEA (29 mL, 2 1 .5 g, 1 66 mmol) to a solution of 3-methoxyazetidine hydrochloride ( 1 8.7 g, 15 1 mmol) in MeOH (280 mL) and stir at RT for 30 minutes. Add this mixture to 5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methy ]-3-methyl-2-[( 1 R)- 1 -(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (27.55 g, 56.28 mmol), stir at RT for 1 .5 hours under N2 and then add TH F (50 mL). Cool the reaction to -70 °C and add 2M L1BH4 in TH F (40 mL, 80 mmol) over 30 minutes. Stir the reaction at the same temperature for 2 hr. Quench the reaction by slowly pouring the reaction into \ M aqueous HCl solution (about 1 L) over 10 minutes. Wash with MTBE (2 x 0.25 L), then treat the aqueous phase with 2M aqueous K3PO4 to pH 9 and extract with EtOAc (about 0.5 L). Wash the organic phase sequentially with 3M aqueous K2C03 and saturated aqueous NaCl (each about 100 mL), dry over Na2S04, filter and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 10-25% of a 20% solution of 7NNH3/MeOH in EtOAc to give the title compound as a white solid ( 19.5 g, 68% yield). ES/MS (m/z): 5 12 (M+H).

Preparation 94

5-[2-Methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-2-[(lR)-l-{trans-4-[3-(3- methyl- 1 H-pyrazol- 1 -yl)azetidin- 1 -yljcyclohexyl } ethyl] -6,7-dihydrothieno[3 ,2- c]pyridine-4(5H)-one

and

5-[(2-methoxy-4,6-dimethyl-3-pyridyl)methyl]-3-methyl-2-[(lR)-l-[trans-4-[3-(5- methylpyrazol-l-yl)azetidin-l-yl]cyclohexyl]ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4- one (mixture of regioisomers)

Stir a solution of a mixture of 1 -(azetidin-3-yl)-3-methyl- l H-pyrazole and 1 -(azetidin-3-yl)-5-methyl-pyrazole (0.53 g, 3.59 mmol, mixture of regioisomers), DIPEA ( 1 .37 mL, 7.79 mmol) and 4N HC1 in dioxane ( 1 .8 mL, 7.190 mmol) in MeOH (5 mL) for 30 min at RT. Add this to a solution of 5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-2-[(lR)-l-(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (600 mg, 1.2 mmol) in MeOH ( 19 mL) and stir 2 hr at RT. Cool the mixture to -78 °C and add a solution of 2M Li BH4 in THF (0.78 mL, 1 .56 mmol); gradually warm to RT and stir the reaction mixture overnight. Concentrate the reaction mixture in vacuo.

Subject the resulting residue to chromatography over SCX (25 g cartridge), eluting with MeOH (2 x 100 mL) followed by a solution of 2NNH3 in MeOH. Concentrate the MeOH in NH3 fraction in vacuo to give the title compound as a mixture of regioisomers as pale yellow oil (0.51 g, 65% yield). ES/MS (m/z): 562 (M+H).

Prepare the following compounds essentially by the method of Preparation 94 using 5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-2-[(lR)-l-(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one and the appropriately substituted azetidine.

Preparation 99

5- [(2-Methoxy-4,6-dimethylpyridin-3-yl)methyl] -2- [( 1 R)- - {4-[3-(2- methoxyethoxy)azetidin- l -yl]cyclohexyl ethy]]-3-methyl-6,7-dihydrothieno[3,2- c]pyridin-4(5 H )-one (mixture of diastereomers)

Add DIPEA (0.45 mL, 2.49 mmol) to a solution of 3-(2-methoxyethoxy)azetidine hydrochloride (0.42 g, 2.38 mmol,) in MeOH (5.6 mL) and stir at RT for 30 min. Add 5-[(2-methoxy-4,6-dimethylpyridin-3 -yl)methyl]-3-methyl-2-[( 1 R)- 1 -(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.62 g, 1 .12 mmol) and stir at RT overnight. Cool the mixture to -78 °C, add a 2M solution of LiBH4 in THF (0.74 mL, 1 .47 mmol), warm to RT, and stir overnight. Add saturated aqueous NaHC03 solution, extract with EtOAc, and separate the layers. Dry the organic phase over Na2S04, filter, and concentrate the filtrate in vacuo to afford title compound as oil (0.5 g, 98% yield). ES/MS (m/z): 556 (M+H).

Preparation 100

2-{(lR)-l-[Trans-4-(benzylamino)cyclohexyl]ethyl}-5-[(2-methoxy-4,6-dimethylpyridin- 3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

Stir a solution of benzyl amine (0.257 g, 2.397 mmol), DIPEA (0.95 mL, 5.39 1) and 4N HC1 in dioxane (600 μί, 2.397 mmol) in MeOH (5 mL) for 30 min at RT.

Add this mixture to a solution of the 5- [(2-methoxy-4,6-dimethyl pyridin-3 -yl)methy 1] -3 -methyl-2-[( l R)- l -(4-oxocyclohexyl)ethyl]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.6 g, 1.2 mmol) in MeOH ( 19 mL) and stir the resulting mixture for 18 hr at RT. Cool the mixture to -70 °C and add a solution of 2M LiBH4 in THF (0.78 mL, 1.558 mmol). Allow to gradually warm up to room temperature. Add an ice-cold saturated NaHC03 solution, extract with EtOAc ( 100 mL), separate the layers, wash the organic extract with saturated aqueous NaCl, and dry the organic extract over Na2S04. Filter and concentrate the filtrate in vacuo to afford the title compound as yellow oil (0.75 g, 99% yield) suitable for use without additional purification. ES/MS (m/z): 532 (M+H).

Preparation 101

2-[( 1 R)- 1 -(Trans-4-aminocyclohexyl)ethyl]-5-[(2-methoxy-4,6-dimethylpyridin-3- yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

Stir a solution of 2-{(lR)-l-[trans-4-(benzylamino)cyclohexyl]ethyl}-5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (750 mg, 1 .19 mmol) in MeOH (20 mL). Add 10% Pd-C (500 mg, 0.474 mmol) and stir under H2 at 30 psi at RT overnight. Filter through diatomaceous earth and wash with MeOH. Evaporate the filtrate to afford the title compound as yellow oil (0.5 g, 80% yield), suitable for use without additional purification. ES/MS (m/z): 442 (M+H).

Preparation 102

2-{(lR)-l-[Trans-4-(dimethylamino)cyclohexyl]ethyl}-5-[(2-methoxy-4,6- dimethylpyridin-3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

Stir a solution of 2-[( 1 )- 1 -(trans-4-aminocyclohexyl)ethyl]-5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.5 g, 0.95 mmol) in MeOH ( 10 mL). Add AcOH ( 172 mg, 2.85 mmol), 37% aqueous formaldehyde (232 mg, 2.853 mmol). Cool the solution with an ice bath and add triacetoxyborohydride (605 mg, 2.853 mmol). Allow to gradually warm to RT and stir overnight. Add ice-cold saturated NaHCOi solution, and extract with DCM (2 x 100 mL). Separate the layers, combine the organic phases, and wash the combined organic extracts with saturated aqueous NaCl. Dry over NaiSC , filter, and concentrate the filtrate in vacuo to afford the title compound as yellow oil (390 mg, 70% yield), suitable for use without additional purification. ES/MS (m/z): 470 (M+H).

Preparation 103

5-{[2-(Benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-2-[l,4-dioxaspiro[4.5]dec-8- yl(methyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

To 2-[ l ,4-dioxaspiro[4.5]dec-8-yl(methyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.5 1 g, 1 .53 mmol) in THF (5 mL) at 0 °C, add a solution of 1 KHMDS in THF (2.14 mL, 2.14 mmol). Warm to RT and after 15 min add 2-benzyloxy-3-(chloromethyl)-4,6-dimethyl-pyridine (0.60 g, 2.29 mmol). Stir at RT for about 17 hr, then quench with saturated aqueous NH4C1 solution ( 1 mL). Dilute the mixture with EtOAc (40 mL) and water (5 mL), separate the organic layer, dry over Na2S04, filter, and concentrate the filtrate in vacuo to afford the title compound (0.94 g, 92% yield) as yellow oil, suitable for use without additional purification. ES/MS (m/z): 562 (M+H).

Preparation 104

5-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-methyl-2-[methyl(4- oxocyclohexyl)amino]-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

To crude 5 - { [2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl} -2- [ 1 ,4-dioxaspiro[4.5]dec-8-yl(methyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (0.94 g, 1 .4 mmol) in TH F ( 14 mL), add IM aqueous HCl ( 14 mL, 14 mmol), heat the mixture to 50 °C for 8 hr and stir at RT for 2 days. Add solid NaHC03 ( 1 .8 g, 2 1 mmol) and EtOAc ( 125 mL), separate the organic layer, and dry over Na2S04. Filter and concentrate the filtrate in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 0- 10% IN methanolic NH3 in DCM, to afford the title compound (0.408 g, 62% yield) as yellow foam after solvent evaporation. ES/MS (m/z): 428 (M+H).

Preparation 105

2-[ l ,4-Dioxaspiro[4.5]dec-8-yl(ethyl)amino]-5-[(2-methoxy-4,6-dimethylpyridin-3- yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

In two separate batches, add a 0.91 M solution of potassium

bis(trimethylsilyl)amide in TH F (22 mL, 20 mmol) slowly to a solution of 2-[ l ,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (6 g, 1 7. 1 2 mmol) in TH F (70 mL) at RT over 30 min. Stir the resulting mixtures for an additional 30 min at RT, then drop wise add 3-(chloromethyl)-2-methoxy-4,6-dimethyl-pyridine (3.4 g, 18 mmol) in THF ( 10 mL). Stir the resulting mixtures at RT overnight. Combine both mixtures, pour into an ice-cold saturated aqueous NaHC03 solution, and extract with EtOAc. Separate the phases, dry the organic extract over MgS04, filter, and concentrate the filtrate in vacuo to afford the title compound (total 18.55 g, quantitative yield) as yellow gum, suitable for use without additional purification. ES/MS (m/z): 500 (M+H).

Preparation 106

2-[Ethyl(4-oxocyclohexyl)amino]-5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3- methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one

O

Add 6M aqueous HC1 (20 mL, 120 mmol) to solution of crude 2-[ l ,4-dioxaspiro[4.5]dec-8-yl(ethyl)amino]-5-[(2-methoxy-4,6-dimethylpyridin-3-yl)methyl]-3-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one ( 1 8.05 g, 36.12 mmol) in THF (20 mL). Heat the resulting mixture at 50 °C for 2 hr, and stir at RT overnight. Pour the reaction mixture into ice-cold saturated aqueous NaHC03, extract with DCM, separate the layers, and concentrate the organic layer in vacuo. Subject the resulting residue to chromatography on silica, eluting with a gradient of 10-50% EtOAc in hexanes to afford the title compound (4.01 g, 24% yield) as light yellow oil after solvent evaporation.

WE CLAIM:

1. A compound of the formula:

wherein:

X is -CH2- or -CH2-CH2-;

Y' is -NR4R5, -CH(CH3)-cyclohexyl-4-yl-N-methyl-N-methoxyethyl, or -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy,

cyclopropylmethoxy, pyrazolyl, methylpyrazolyl, triazolyl, pyrrolidinyl,

tetrahydrofuranyloxy, or mo holinyl;

R4 is cyclohex-4-yl substituted with N-methyl-N-methoxyethy amino, N -methyl -N-cyclopropylamino, or azetidin- 1 -yl wherein the azetidin- 1 -yl is substituted with methoxy, ethoxy, methoxyethoxy, cyclopropyloxy, or pyrazolyl;

R5 is methyl or ethyl; and

R6 is methyl or chloro; or a pharmaceutically acceptable salt thereof.

2. The compound or salt thereof according to Claim 1 , wherein X is -CH2-.

3. The compound or salt thereof according to Claim 1 , wherein X is -CH2- CH2-.

4. The compound or salt thereof according to any one of Claims 1 -3 wherein

Y' is -CH(CH3)-cyclohexyl-4-yl-N-methyl-N-methoxyethyl or -CH(CH3)-cyclohex-4-yl-azetidin- 1 -yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, pyrazolyl, methylpyrazolyl, triazolyl, pyrrolidinyl, tetrahydrofuranyloxy, or morpholinyl.

5. The compound or salt thereof according to any one of Claims 1 -4 wherein

Y' is -CH(CH3)-cyclohex-4-yl-azetidin-l-yl wherein the azetidin- 1 -yl is optionally substituted with methoxy, 2-propoxy, methoxymethyl, methoxyethoxy, cyclopropyloxy, cyclopropylmethoxy, pyrazolyl, methylpyrazolyl, triazolyl, pyrrolidinyl,

tetrahydrofuranyloxy, or morpholinyl.

6. The compound or salt according to any one of Claims 1-5 wherein R6 is methyl.

7. The compound or salt thereof according to any one of Claims 1 -3 wherein

Y' is -NR4R5.

8 The compound according to any one of Claims 1 , 3, or 4-6 which is

O

or a phannaceutically acceptable salt thereof.

9. The compound according to Claim 8 which is 5-[(4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3 -yl)methyl] -2-{( l R)- l -[4-(3 -methoxyazetidin- 1 -yljcyclohexyl] ethyl } -3 -methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, or a pharmaceutically acceptable salt thereof.

10. The compound according to Claim 9 which is 5-[(4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3 -yl jmethyl] -2- {( 1 R)- 1 -[trans-4-(3-methoxyazetidin- 1 -yl)cyclohexyl]ethyl}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, or a pharmaceutically acceptable salt thereof.

1 1 . A pharmaceutical composition comprising the compound or salt thereof according to any one of Claims 1 - 10 and one or more pharmaceutically acceptable excipients, carriers, or diluents.

12. A method of treating cancer in a patient, wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SN F complex, MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer comprising administering to the patient, an effective amount of the compound or salt thereof according to any one of Claims 1 - 10.

13. The method according to Claim 12 wherein the cancer is diffuse large B-cell lymphoma and follicular lymphoma.

14. The method according to either Claim 12 or 13 wherein the cancer is diffuse large B-cell lymphoma.

15. The method according to Claim 12 wherein the cancer is a rhabdoid tumor that lacks SNF5.

16. The method according to Claim 12 wherein the cancer is gastric cancer.

17. The method according to Claim 12 wherein the cancer is ovarian cancer.

18. The method according to Claim 12 wherein the cancer is multiple myeloma.

19. A method of treating ovarian cancer in a patient comprising administering to the patient a compound or salt thereof according to any one of Claims 1 - 10 in combination with carboplatin and paclitaxel.

20. A method of treating gastric cancer in a patient comprising administering to the patient a compound or salt thereof according to any one of Claims 1 - 10 in combination with oxaliplatin and paclitaxel.

21. A method of treating lung cancer in a patient comprising administering to the patient a compound or salt thereof according to any one Claims 1 - 10 in combination with gemcitabine and cisplatin.

22. A method of treating colorectal cancer in a patient comprising

administering to the patient a compound or salt thereof according to any one of Claims 1 - 10 in combination with irinotecan and oxaliplatin.

23. The compound or salt thereof according to any one of Claims 1 - 10 for use in therapy.

24. The compound or salt thereof according to any one of Claims 1 - 10 for use in the treatment of cancer.

25. The compound or salt thereof for use according to Claim 24 wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SNF complex, MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer.

26. The compound or salt thereof for use according to Claim 25, wherein the cancer is diffuse large B-cell lymphoma or follicular lymphoma.

27. The compound or salt thereof for use according to either Claim 25 or 26, wherein the cancer is diffuse large B-cell lymphoma.

28. The compound or salt thereof for use according to Claim 26, wherein the cancer is a rhabdoid tumor that lacks SNF5.

29. The compound or salt thereof for use according to Claim 26, wherein the cancer is gastric cancer.

30. The compound or salt thereof for use according to Claim 26, wherein the cancer is ovarian cancer.

31 . The compound or salt thereof for use according to Claim 26, wherein the cancer is multiple myeloma.

32. A combination comprising a compound or salt thereof according to any one of Claims 1-10 and carboplatin and paclitaxel for simultaneous, separate, or sequential use in the treatment of ovarian cancer.

33. A compound or salt thereof according to any one of Claims 1 - 10 for use in simultaneous, separate or sequential combination with carboplatin and paclitaxel in the treatment of ovarian cancer.

34. Carboplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one of Claims 1 - 10 and paclitaxel in the treatment of ovarian cancer.

35. Paclitaxel for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one of Claims 1 - 10 and carboplatin in the treatment of ovarian cancer.

36. A combination comprising a compound or salt thereof according to any one of Claims 1 - 10 and oxaliplatin and paclitaxel for simultaneous, separate, or sequential use in the treatment of gastric cancer.

37. A compound or salt thereof according to any one of Claims 1 - 10 for use in simultaneous, separate or sequential combination with oxaliplatin and paclitaxel in the treatment of gastric cancer.

38. Oxaliplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one Claims 1 - 10 and paclitaxel in the treatment of gastric cancer.

39. Paclitaxel for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one of Claims 1 - 10 and oxaliplatin in the treatment of gastric cancer.

40. A combination comprising a compound or salt thereof according to any one ofClaims 1 - 10 and gemcitabine and cisplatin for simultaneous, separate, or sequential use in the treatment of lung cancer.

41 . A compound or salt thereof according to any one of C laims 1 - 10 for use in simultaneous, separate or sequential combination with gemcitabine and cisplatin in the treatment of lung cancer.

42. Gemcitabine for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one ofClaims 1 - 10 and cisplatin in the treatment of lung cancer.

43. Cisplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one ofClaims 1 - 10 and gemcitabine in the treatment of lung cancer.

44. A combination comprising a compound or salt thereof according to any one ofClaims 1 - 10 and irinotecan and oxaliplatin for simultaneous, separate, or sequential use in the treatment of colorectal cancer.

45. A compound or salt thereof according to any one of Claims 1 - 10 for use in simultaneous, separate or sequential combination with irinotecan and oxaliplatin in the treatment of colorectal cancer.

46. Irinotecan for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one ofClaims 1 - 10 and oxaliplatin in the treatment of colorectal cancer.

47. Oxaliplatin for use in simultaneous, separate, or sequential combination with a compound or salt thereof according to any one ofClaims 1 - 10 and irinotecan in the treatment of colorectal cancer.

48. The combination, oxaliplatin, gemcitabine, paclitaxel, the compound or salt thereof, irinotecan, cisplatin, or carboplatin for use according to any one of Claims 32-47.