Phenylalanine derivatives and their use as non-peptide GLP-1 receptor modulators

A compound of Formula (I):

• or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
• wherein:
• A is C3-8 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• E is a bond, C2-6 alkenylene, C2-6 alkynylene, arylene, heteroarylene, carbocyclylene, heterocyclylene;
• with the proviso that E is not 4-oxo-imidazolidinylene;
• L3 is a bond, —C(O)—, —O—, —OC(O)O—, —OC(O)NR1a—, —NR1aC(O)O—, —OS(O)—, —S(O)O—, —OS(O)2—, —S(O)2O—, —OS(O)NR1a—, —NR1aS(O)O—, —OS(O)2NR1a—, —NR1aS(O)2O—, —NR1a—, —NR1aC(O)NR1d—, —NR1aS(O)NR1d—, —NR1aS(O)2NR1d—, —S—, —S(O)—, —S(O)2—, —S(O)NR1a—, —NR1aS(O)—, —S(O)2NR1a—, or —NR1aS(O)2—;
• with the provisos that (a) E and L3 are not both a bond at the same time;
• and (b) when L3-E together is —O—, R6 is not iodo or benzoxy;
• m is an integer of 0, 1, 2, 3, or 4;
• L1 is a carboxylate bioisostere selected from the group consisting of —CH2OH, —CONH2, —CO2H, —P(O)(OH)2, —P(OH)2, tetrazolyl, or 3-hydroxyisoxazolyl;
• L2 is —CH2N(R5)—, —N(R5)CH2—, —N(R5)—, —O—, —S—, —C(O)NR5—, —NR5C(O)—, —CH2C(O)NR5—, —NR5C(O)CH2—, —CH═CH—C(O)NR5—, —NR5C(O)—CH═CH—, —C≡C—C(O)NR5—, —NR5C(O)—C≡C—, —S(O)NR5—, —NR5S(O)—, —S(O)2NR5—, —NR5S(O)2—, —NR5C(O)NR5a—, —NR5S(O)2NR5a—, —CH2NR5S(O)2NR5a—, —NR5S(O)2NR5aCH2—, —NR5C(O)-alkylene, —NR5S(O)-alkylene, —NR5S(O)2-alkylene, —NR5C(O)-alkenylene, —NR5S(O)-alkenylene, or —NR5S(O)2-alkenylene;
• or alternatively;
• or alternatively, L2 and V or W, together with other atoms to which they are attached, form 5- to 8-membered optionally substituted carbocyclyl or heterocyclyl;
• or alternatively, V or W and the carbon atom which is attached to R3, L1, and L2, together with other atoms to which they are attached, form 5- to 8-membered optionally substituted carbocyclyl or heterocyclyl;
• U, V, W, X, and Y are each independently C, CH, or N;
• and U, V, W, X, and Y, together with the carbon atom to which V and W are attached, form an aromatic 6-membered ring;
• with the proviso that at most 3 of U, V, W, X, and Y are N or NH;
• R1, R2, and R3 are selected from (i), (ii), (iii), and (iv):
• (i) R1, R2, and R3 are each independently (a) hydrogen, halo, or cyano;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• (ii) R1 or R2 forms a double bond with R3;
• and the other of R1 and R2 is selected as in (i);
• (iii) two of R1, R2, and R3 are joined together to form C3-8-carbocyclyl, or 3- to 8-membered heterocyclyl;
• and the third is selected as in (i);
• and
• (iv) R3 and V or W, together with the other atoms to which are attached, form C5-8 carbocyclyl, or 5- to 8-membered heterocyclyl;
• and R1 and R2 are selected as in (i);
• R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or alternatively, R4 and R5 together with the N atom to which they are attached form heterocyclyl;
• R5 and R5a are each independently hydrogen, C1-6 alkyl, —C(O)—C1-6 alkyl;
• C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or alternatively, R4 and R5 are joined together to form heterocyclyl;
• R6 is cyano, halo, azido, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, heterocyclyl, —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• when U, V, W, X, and Y are each independently C or CH;
• R1, R2, and R3 are hydrogen;
• L1 is —CONH2 or —CO2H;
• L2 is —NR5C(O)—;
• and R4 is -heteroaryl-aryl;
• then A-L3-E- is cyano group;
• each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl;
• or R1b and R1c together with the N atom to which they are attached form heterocyclyl;
• wherein each alkyl, alkenyl, alkenylene, alkynyl, alkynylene, carbocyclyl, carbocyclylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene, in R1, R2, R3, R4, R5, R5a, R6, R1a, R1b, R1c, R1d, A, and E is optionally substituted with one or more substituents Q, where each Q is independently selected from
• (a) cyano, halo, azido, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• and
• (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
• and
• wherein each Qa is independently selected from the group consisting of (a) cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(NRe)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(═NRe)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(═NRh)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
• wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.