Provided herein are pharmaceutical compositions that are useful for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

Provided herein are pharmaceutical compositions that are useful for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

Provided herein are pharmaceutical compositions that are useful for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

Provided herein are pharmaceutical compositions that are useful for the treatment of hypertension comprising an angiotensin II receptor blocker, a diuretic, and a calcium channel blocker.

The present technology provides methods for treating pancreatic cancer using a MEK inhibitor and a CDK4/6 inhibitor. Also disclosed herein are methods for increasing patient responsiveness to chemotherapeutic and/or immunotherapeutic regimes for pancreatic cancer. Kits for use in practicing the methods are also provided.

The present technology provides methods for treating pancreatic cancer using a MEK inhibitor and a CDK4/6 inhibitor. Also disclosed herein are methods for increasing patient responsiveness to chemotherapeutic and/or immunotherapeutic regimes for pancreatic cancer. Kits for use in practicing the methods are also provided.

The present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, wherein: the group X-Y is —NHSO.sub.2— or —SO.sub.2NH—; R.sub.1 is H or alkyl; R.sub.2 is selected from COOH and a tetrazolyl group; R.sub.3 is selected from H, Cl and alkyl; R.sub.4 is selected from H, Cl and F; R.sub.5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO.sub.2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R.sub.6 is H; R.sub.7 is selected from H, CN, haloalkyl, Cl, F, SO.sub.2-alkyl, SO.sub.2NR.sub.13R.sub.14, optionally substituted heteroaryl and alkyl; R.sub.8 is selected from H, alkyl, haloalkyl and halo; R.sub.9 is H, C.sub.1-C.sub.3-alkyl, or halo; R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an azepanyl group, wherein (a) said azepanyl group is substituted by one or more substituents, or (b) one or two carbons in said azepanyl group are replaced by a group selected from O, NH, S and CO, and said azepanyl group is optionally further substituted; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl or piperidinyl group wherein (a) said azetidinyl, pyrrolidinyl or piperidinyl group is substituted by one or more substituents, or (b) one or two carbons in said azetidinyl, pyrrolidinyl or piperidinyl group are replaced by a group selected from NH, S and CO; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an 8, 9 or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic heterocycloalkyl group is optionally substituted; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a 6 to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic group is optionally substituted, or said bicyclic group is optionally fused to a 5 or 6-membered aryl or heteroaryl group; R.sub.13 and R.sub.14 are each independently H or alkyl. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.

##STR00001##

The present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, wherein: the group X-Y is —NHSO.sub.2— or —SO.sub.2NH—; R.sub.1 is H or alkyl; R.sub.2 is selected from COOH and a tetrazolyl group; R.sub.3 is selected from H, Cl and alkyl; R.sub.4 is selected from H, Cl and F; R.sub.5 is selected from H, alkyl, alkynyl, alkenyl, haloalkyl, SO.sub.2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R.sub.6 is H; R.sub.7 is selected from H, CN, haloalkyl, Cl, F, SO.sub.2-alkyl, SO.sub.2NR.sub.13R.sub.14, optionally substituted heteroaryl and alkyl; R.sub.8 is selected from H, alkyl, haloalkyl and halo; R.sub.9 is H, C.sub.1-C.sub.3-alkyl, or halo; R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an azepanyl group, wherein (a) said azepanyl group is substituted by one or more substituents, or (b) one or two carbons in said azepanyl group are replaced by a group selected from O, NH, S and CO, and said azepanyl group is optionally further substituted; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl or piperidinyl group wherein (a) said azetidinyl, pyrrolidinyl or piperidinyl group is substituted by one or more substituents, or (b) one or two carbons in said azetidinyl, pyrrolidinyl or piperidinyl group are replaced by a group selected from NH, S and CO; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an 8, 9 or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic heterocycloalkyl group is optionally substituted; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a 6 to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic group is optionally substituted, or said bicyclic group is optionally fused to a 5 or 6-membered aryl or heteroaryl group; R.sub.13 and R.sub.14 are each independently H or alkyl. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.

##STR00001##

The present disclosure provides compounds according to Formula I and pharmaceutically acceptable salts thereof, as well as compositions including such compounds and a pharmaceutically acceptable carrier or excipient. Further provided are methods of inactivating SIRT6 with compounds of Formula I as well as compounds of Formula III, W.sup.2—R.sup.2—Y—R.sup.3, as described herein. In addition, the present technology provides methods of treatment using such compounds to lower LDL levels, lower triglyceride levels, and/or increase glucose tolerance in a subject, and/or to inhibit proliferation of ovarian, colorectal, hepatocellular, non-small cell lung, glioblastoma, osteosarcoma, pancreatic, and skin cancer cells, and/or inhibit liver and/or kidney fibrosis, and/or promote corneal epithelial wound healing.

The present disclosure provides compounds according to Formula I and pharmaceutically acceptable salts thereof, as well as compositions including such compounds and a pharmaceutically acceptable carrier or excipient. Further provided are methods of inactivating SIRT6 with compounds of Formula I as well as compounds of Formula III, W.sup.2—R.sup.2—Y—R.sup.3, as described herein. In addition, the present technology provides methods of treatment using such compounds to lower LDL levels, lower triglyceride levels, and/or increase glucose tolerance in a subject, and/or to inhibit proliferation of ovarian, colorectal, hepatocellular, non-small cell lung, glioblastoma, osteosarcoma, pancreatic, and skin cancer cells, and/or inhibit liver and/or kidney fibrosis, and/or promote corneal epithelial wound healing.