Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

Compounds of general formula (I): wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5.sup.a, R* X.sup.1, X.sup.2, Z and Y are as defined herein are positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. The compounds are useful for treating diseases and conditions affected by modulation of TMEM16A, particularly respiratory diseases and conditions. ##STR00001##

A composition in the form of an injectable aqueous solution, wherein the pH is comprised from 6.0 to 8.0, includes at least: a) amylin, an amylin receptor agonist or an amylin analog; and b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, wherein the composition does not comprise a basal insulin wherein the isoelectric point pI is comprised from 5.8 to 8.5. The composition may further include a prandial insulin.

A composition in the form of an injectable aqueous solution, wherein the pH is comprised from 6.0 to 8.0, includes at least: a) amylin, an amylin receptor agonist or an amylin analog; and b) a co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy, wherein the composition does not comprise a basal insulin wherein the isoelectric point pI is comprised from 5.8 to 8.5. The composition may further include a prandial insulin.

Compounds of general formula (I): wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5a, R.sup.5b X.sup.1, X.sup.2, Z and Y are as defined herein are positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. The compounds are useful for treating diseases and conditions affected by modulation of TMEM16A, particularly respiratory diseases and conditions.

##STR00001##

The present invention provides a method for preparing a high-performance graphite sheet by imidizing a polyamic acid resulting from a reaction of dianhydride monomer(s) and diamine monomer(s) to obtain a polyimide film; and carbonizing and/or graphitizing the polyimide film to obtain a high-performance graphite sheet, where the polyimide film contains 2 or more fillers having different average particle diameters, and the thermal conductivity of the graphite sheet is at least 1,400 W/m.Math.K. Further, the present invention provides a graphite sheet obtained by the above method.

The present invention provides a method for preparing a high-performance graphite sheet by imidizing a polyamic acid resulting from a reaction of dianhydride monomer(s) and diamine monomer(s) to obtain a polyimide film; and carbonizing and/or graphitizing the polyimide film to obtain a high-performance graphite sheet, where the polyimide film contains 2 or more fillers having different average particle diameters, and the thermal conductivity of the graphite sheet is at least 1,400 W/m.Math.K. Further, the present invention provides a graphite sheet obtained by the above method.

The present disclosure provides a benzene fused heterocyclic derivative of Formula (I): is a single or double bond; n is an integer of 0 or 1; A is —CH.sub.2—, —CH(OH)—, or —C(O)—; G is C or N; X is —CH.sub.2—, O, or —C(O)—; Y is alkyl, aryl, or heterocyclic alkyl optionally substituted with at least one substituent independently selected from a group consisting of: H, halogen, alkyl, alkyl substituted with at least one halogen, aryl, aryl substituted with at least one halogen, —NR.sub.y1R.sub.y2, —OR.sub.y1, —R.sub.y1C(O)R.sub.y3, —C(O)R.sub.y1, —C(O)OR.sub.y2, —C(O)OR.sub.y2Ry3, —NR.sub.y1C(O)R.sub.y2, —NR.sub.y1C(O)NR.sub.y2R.sub.y3, —NR.sub.y1C(O)OR.sub.y2R.sub.y3, —NR.sub.y1C(O)R.sub.y2OR.sub.y3, C(O)NR.sub.y1(R.sub.y2R.sub.y3), —C(O)NR.sub.y1(R.sub.y2OR.sub.y1), —OR.sub.y2R.sub.y3, and —OR.sub.y2OR.sub.y3, wherein each of R.sub.y1 and R.sub.y2 is independently selected from a group consisting of H, oxygen, alkyl, and aryl, and R.sub.y3 is aryl optionally substituted with at least one halogen; Z is —NR.sub.z1R.sub.z2, —NR.sub.z1R.sub.z3, —OR.sub.z1, —OR.sub.z1R.sub.z3, —C(O)R.sub.z1R.sub.z3, —C(O)OR.sub.z1R.sub.z3, —NR.sub.z1C(O)R.sub.z2R.sub.z3, —NR.sub.z1C(O)OR.sub.z2R.sub.z3, —C(O)NR.sub.z1R.sub.z3, or OR.sub.z2OR.sub.z3, wherein each of R.sub.z1 and R.sub.z2 is independently selected from a group consisting of H, oxygen, alkyl and aryl, and R.sub.z3 is aryl optionally substituted with at least one substituent independently selected from a group consisting of halogen, OH, —R.sub.zaCOOR.sub.zb, —OR.sub.zaCOOR.sub.zb, —R.sub.zaSO.sub.2R.sub.zb, —R.sub.zaSO.sub.2NR.sub.zbR.sub.zcR.sub.zd, —R.sub.zaC(O)R.sub.zbR.sub.zc, —R.sub.zaC(O)NR.sub.zbR.sub.zcR.sub.zd, —RZ.sub.aC(O)NR.sub.zbSO.sub.2R.sub.zc, wherein Rza is nil or alkyl, R.sub.zb is H or alkyl, each of R.sub.zb and R.sub.zc is independently selected from a group consisting of H, OH, alkyl, aryl, alkoxyl, or NR.sub.zbR.sub.zc is a nitrogen-containing heterocyclic alkyl ring, R.sub.zd is nil or a sulfonyl alkyl group. ##STR00001##

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.

The present invention provides cationic lipids and lipid nanoparticle formulations comprising these lipids, alone or in combination with other lipids. These lipid nanoparticles may be formulated with nucleic acids to facilitate their intracellular delivery both in vitro and for therapeutic applications. The present invention also provides methods of chemical synthesis of these lipids, lipid nanoparticle preparation and formulation with nucleic acids.