In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: Formula AA or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.

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In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: Formula AA or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.

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The present invention relates to a pharmaceutical composition comprising a combination of an FXR agonist and at least one lipid lowering agent (e.g., PPAR-alpha agonist, PPAR-delta agonist, PPAR-alpha and delta dual agonist, and/or statin). Also disclosed is use of the combination for the treatment or prevention of a FXR mediated disease or condition, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, NAFLD (nonalcoholic fatty liver disease), NASH (non-alcohol-induced steatohepatitis), and other chronic liver diseases. The combination of the present invention is useful for the treatment or prevention of conditions related to elevated lipid and liver enzyme levels. The present invention also relates to packs or kits including the pharmaceutical combination.

The present invention relates to a pharmaceutical composition comprising a combination of an FXR agonist and at least one lipid lowering agent (e.g., PPAR-alpha agonist, PPAR-delta agonist, PPAR-alpha and delta dual agonist, and/or statin). Also disclosed is use of the combination for the treatment or prevention of a FXR mediated disease or condition, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), portal hypertension, bile acid diarrhea, NAFLD (nonalcoholic fatty liver disease), NASH (non-alcohol-induced steatohepatitis), and other chronic liver diseases. The combination of the present invention is useful for the treatment or prevention of conditions related to elevated lipid and liver enzyme levels. The present invention also relates to packs or kits including the pharmaceutical combination.

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, A compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, (I) wherein: Z is a group of formula: (II) wherein P and Q are each independently CR.sub.12R.sub.13; or one of P and Q is NR.sub.14 and the other is CR.sub.12R.sub.13; the group X—Y is —NHSO.sub.2— or —SO2NH—; R.sub.1 is H, CN 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 and halo; R.sub.5 is selected from H, alkyl, 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, halo, SO.sub.2-alkyl, heteroaryl, SO.sub.2NR.sub.16R.sub.17, CONR.sub.10R.sub.11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R.sub.8 is selected from H, alkyl, haloalkyl and halo; R.sub.9 is H or halo; and R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.16 and R.sub.17 are each independently H or alkyl; R.sub.15 is selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m and n are each independently 0, 1, 2 or 3. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.

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The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, A compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, (I) wherein: Z is a group of formula: (II) wherein P and Q are each independently CR.sub.12R.sub.13; or one of P and Q is NR.sub.14 and the other is CR.sub.12R.sub.13; the group X—Y is —NHSO.sub.2— or —SO2NH—; R.sub.1 is H, CN 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 and halo; R.sub.5 is selected from H, alkyl, 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, halo, SO.sub.2-alkyl, heteroaryl, SO.sub.2NR.sub.16R.sub.17, CONR.sub.10R.sub.11 and alkyl, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R.sub.8 is selected from H, alkyl, haloalkyl and halo; R.sub.9 is H or halo; and R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.16 and R.sub.17 are each independently H or alkyl; R.sub.15 is selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; and m and n are each independently 0, 1, 2 or 3. Further aspects of the invention relate to such compounds for use in the field of immune-oncology and related applications.

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Disclosed is method of treating a patient having rheumatoid arthritis, comprising administering sequentially to said patient, a therapeutically effective dose of branebrutinib for a first period, followed by a therapeutically effect dose of abatacept for a second period.

Disclosed is method of treating a patient having rheumatoid arthritis, comprising administering sequentially to said patient, a therapeutically effective dose of branebrutinib for a first period, followed by a therapeutically effect dose of abatacept for a second period.

Described herein is a multiplexed and high content screening assay using primary neurons for identifying small molecule modulators of neuronal mitochondrial mitostasis (MnMs). Also described is a high throughput screening assay using primary neurons for identifying small molecules that increase mitochondrial function, identified by measuring the electrochemical potential across the inner mitochondrial membrane and ATP generation. Most MnMs that increased mitochondrial content, length and/or health also increased mitochondrial function without altering neurite outgrowth. Some MnMs protect mitochondria in primary neurons from Aβ(1-42) toxicity, glutamate toxicity, increased oxidative stress and the toxic cellular environment associated with Alzheimer's disease. Some MnMs target mitochondria directly. An MnM also increases the synaptic activity of hippocampal neurons and is potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. The MnMs were demonstrated to protect the mitochondrial population in neurons in an in vivo model of Alzheimer's Disease. Also described is a method for treating a patient suffering from a disorder characterized by dysfunction of neuronal mitostasis, comprising administering to the patient a therapeutically effective amount of a compound (MnM), or a pharmaceutically acceptable salt thereof.

Described herein is a multiplexed and high content screening assay using primary neurons for identifying small molecule modulators of neuronal mitochondrial mitostasis (MnMs). Also described is a high throughput screening assay using primary neurons for identifying small molecules that increase mitochondrial function, identified by measuring the electrochemical potential across the inner mitochondrial membrane and ATP generation. Most MnMs that increased mitochondrial content, length and/or health also increased mitochondrial function without altering neurite outgrowth. Some MnMs protect mitochondria in primary neurons from Aβ(1-42) toxicity, glutamate toxicity, increased oxidative stress and the toxic cellular environment associated with Alzheimer's disease. Some MnMs target mitochondria directly. An MnM also increases the synaptic activity of hippocampal neurons and is potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. The MnMs were demonstrated to protect the mitochondrial population in neurons in an in vivo model of Alzheimer's Disease. Also described is a method for treating a patient suffering from a disorder characterized by dysfunction of neuronal mitostasis, comprising administering to the patient a therapeutically effective amount of a compound (MnM), or a pharmaceutically acceptable salt thereof.