The present invention provides an industrially advantageous method for producing a 3,5-disubstituted triazine compound that is useful as an active pharmaceutical ingredient. More specifically, the present invention provides a production method, whereby it becomes possible to efficiently produce a 3-oxo-5-substituted triazine in water without the need to isolate an intermediate that may have mutagenicity, and it also becomes possible to perform the production without the need to isolate a product in each of multiple steps. Namely, the present invention provides a method for producing a compound represented by formula I or a salt thereof, the method including a step of reacting a compound represented by the following formula IV or a salt thereof with a base in water, and optionally including a step of forming a salt thereof. Specifically, the present invention provides a method for producing a compound represented by formula I or a salt thereof, the method including a step of derivatizing a compound represented by formula II or a salt thereof into a corresponding compound represented by formula III, a salt thereof, or a derivative thereof, then a step of reacting the resulting compound, a salt thereof, or a derivative thereof with aminourea or a salt thereof in water to produce a compound represented by formula IV or a salt thereof, and then a step of reacting the resulting compound or a salt thereof in the presence of a base. ##STR00001##
(wherein ring A represents an optionally substituted aryl group or an optionally substituted heteroaryl group)

The present invention provides an industrially advantageous method for producing a 3,5-disubstituted triazine compound that is useful as an active pharmaceutical ingredient. More specifically, the present invention provides a production method, whereby it becomes possible to efficiently produce a 3-oxo-5-substituted triazine in water without the need to isolate an intermediate that may have mutagenicity, and it also becomes possible to perform the production without the need to isolate a product in each of multiple steps. Namely, the present invention provides a method for producing a compound represented by formula I or a salt thereof, the method including a step of reacting a compound represented by the following formula IV or a salt thereof with a base in water, and optionally including a step of forming a salt thereof. Specifically, the present invention provides a method for producing a compound represented by formula I or a salt thereof, the method including a step of derivatizing a compound represented by formula II or a salt thereof into a corresponding compound represented by formula III, a salt thereof, or a derivative thereof, then a step of reacting the resulting compound, a salt thereof, or a derivative thereof with aminourea or a salt thereof in water to produce a compound represented by formula IV or a salt thereof, and then a step of reacting the resulting compound or a salt thereof in the presence of a base. ##STR00001##
(wherein ring A represents an optionally substituted aryl group or an optionally substituted heteroaryl group)

A deuterated compound as represented by formula (I) or an optical isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof are presented. Compared with a compound before deuteration, the deuterated compound shows better pharmacokinetics, higher maximum plasma drug concentration, higher exposure, and longer half-life, and has more excellent metabolic performance. The deuterated compound can effectively inhibit FAK activity, and has good application prospect in preparation of FAK inhibitors and/or drugs for treating cancer. In addition, the use of the deuterated compound in combination with an anti-cancer drug (such as a PD-1 inhibitor) can achieve a synergistic effect, thereby significantly improving the tumor suppression effect, and providing a better choice for clinical cancer treatment.

##STR00001##

The present disclosure relates generally to small molecule modulators of NLR Family Pyrin Domain Containing 3 (NL-RP3), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, methods of making and intermediates thereof, and methods of using thereof.

The present disclosure relates generally to small molecule modulators of NLR Family Pyrin Domain Containing 3 (NL-RP3), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, methods of making and intermediates thereof, and methods of using thereof.

The present invention provides a salt of a triazine compound which has an inhibitory action against aldosterone synthase and is useful as a drug, and especially as a drug for preventing or treating primary aldosteronism and the like, a crystal thereof, and a method for producing the same. Specifically, the present invention provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is hydrobromide, sulfate, succinate, or tosilate, and the like.

The present invention provides a salt of a triazine compound which has an inhibitory action against aldosterone synthase and is useful as a drug, and especially as a drug for preventing or treating primary aldosteronism and the like, a crystal thereof, and a method for producing the same. Specifically, the present invention provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is hydrobromide, sulfate, succinate, or tosilate, and the like.

The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.

The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.

According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A.sub.1-A.sub.2b or, particularly, the A.sub.2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy.sup.1 or Het.sup.A; Cy.sup.1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy.sup.1 group is optionally substituted by one or more R.sup.4a substituents; Het.sup.A represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy.sup.2 or Het.sup.B; Cy.sup.2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy.sup.2 group is optionally substituted by one or more R.sup.4c substituents; Het.sup.B represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which Het.sup.B group is optionally substituted by one or more R.sup.4d substituents. ##STR00001##