	US 12,344,598 B2
	Bis(diazirine) derivatives as photo-crosslinker for treating corneal ectatic disorders
Jason Hill, Auburndale, MA (US); and Desmond Adler, Bedford, MA (US)
Assigned to Avedro, Inc., Waltham, MA (US)
Appl. No. 17/424,413
Filed by Avedro, Inc., Waltham, MA (US)
PCT Filed Jan. 24, 2020, PCT No. PCT/US2020/015071 § 371(c)(1), (2) Date Jul. 20, 2021, PCT Pub. No. WO2020/154673, PCT Pub. Date Jul. 30, 2020.
Claims priority of provisional application 62/796,803, filed on Jan. 25, 2019.
Prior Publication US 2022/0106298 A1, Apr. 7, 2022
Int. Cl. A61P 27/10 (2006.01); C07D 229/02 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01)

CPC C07D 403/12 (2013.01) [A61P 27/10 (2018.01); C07D 229/02 (2013.01); C07D 401/14 (2013.01); C07D 403/14 (2013.01)]

17 Claims

1. A compound of Formula II

or a pharmaceutically acceptable salt thereof,

wherein:

each of B¹and B²is independently —Z¹—Z²—Z³, wherein:

Z¹is C_1-3alkylene;

Z²is a bond; and

Z³is H;

each of E¹and Q¹is C₁-C₆alkylene, which is optionally substituted with 1-3 R^a;

each occurrence of R²is independently selected from the group consisting of:

(i) R^a;

(ii) C₁-C₆alkyl, which is substituted with 1-3 R^a;

(iii) L²-heterocyclyl, wherein the heterocyclyl includes from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N(R^d), O, and S; and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected R^b,

(iv) L²-C₆-C₁₀aryl, which is optionally substituted with from 1-4 R^c;

(v) L²-heteroaryl, wherein the heteroaryl includes from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(R^d), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected R^c; and

(vi) H; or

(vii) R²and R^d1, in the —C(═O)CH(R²)N(R^d1)— group, combine to form a ring including from 5-8 ring atoms, wherein the ring includes: (a) from 3-6 ring carbon atoms (in addition to CH(R²)), each of which is substituted with from 1-2 substituents independently selected from H and C_1-3alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R^d1), which are each independently selected from the group consisting of N(R^d1), O, and S;

each occurrence of R^ais independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR^eR^f; C_1-4alkoxy; C_1-4haloalkoxy; —C(═O)O(C_1-4alkyl); —C(═O)(C_1-4alkyl); —C(═O)OH; —CON(R′)(R″); —S(O)_1-2(NR′R″); —S(O)_0-2(C_1-4alkyl); cyano; —NR′C(═NR′)NR′R″; and C_3-6cycloalkyl optionally substituted with from 1-4 independently selected R^b;

each occurrence of R^bis independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR^eR^f; C_1-4alkyl; C_1-4haloalkyl; C_1-4alkoxy; C_1-4haloalkoxy; —C(═O)O(C_1-4alkyl); —C(═O)(C_1-4alkyl); —C(═O)OH; —CON(R′)(R″); oxo; —S(O)_1-2(NR′R″); —S(O)_0-2(C_1-4alkyl); cyano; —NR′C(═NR′)NR′R″; and C_3-6cycloalkyl optionally substituted with from 1-4 independently selected C_1-4alkyl;

each occurrence of R^cis independently selected from the group consisting of: —OH; —SH; —F; —Cl; —Br; —NR^eR^f; C_1-4alkyl; C_1-4haloalkyl; C_1-4alkoxy; C_1-4haloalkoxy; —C(═O)O(C_1-4alkyl); —C(═O)(C_1-4alkyl); —C(═O)OH; —CON(R′)(R″); —S(O)_1-2(NR′R″); —S(O)_0-2(C_1-4alkyl); cyano; —NR′C(═NR′)NR′R″; and C_3-6cycloalkyl optionally substituted with from 1-4 independently selected C_1-4alkyl;

each occurrence of R^dis selected from the group consisting of: H; C_1-6alkyl; C_3-6cycloalkyl; —C(O)(C_1-4alkyl); —C(O)O(C_1-4alkyl); —CON(R′)(R″); —S(O)_1-2(NR′R″); —S(O)_1-2(C_1-4alkyl); —OH; and C_1-4alkoxy;

each occurrence of R^eand R^fis independently selected from the group consisting of: H; C_1-6alkyl; C_3-6cycloalkyl; —C(O)(C_1-4alkyl); —C(O)O(C_1-4alkyl); —CON(R′)(R″); —S(O)_1-2(NR′R″); —S(O)_1-2(C_1-4alkyl); —OH; and C_1-4alkoxy; and

each occurrence of R′ and R″ is independently selected from the group consisting of: H and C_1-4alkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C_1-3alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(R⁴), O, and S;

each occurrence of R^d1is selected from the group consisting of: H, C_1-6alkyl; C_3-6cycloalkyl; —C(O)(C_1-4alkyl); —C(O)O(C_1-4alkyl); —CON(R′)(R″); —S(O)_1-2(NR′R″); —S(O)_1-2(C_1-4alkyl); —OH; and C_1-4alkoxy; or R²and R^d1, in the —C(═O)CH(R²)N(R^d1)— group, combine to form a ring including from 5-8 ring atoms as defined above;

each of L²in each occurrence is independently a single bond or a C₁-C₆alkylene optionally substituted with 1-3 substituents independently selected from oxo and R^a; and

F¹is —N(R^d1)—, —O—, or —S—; and

each of H¹, G¹, L¹, and M¹is independently selected from:

a bond;

—N(R^d1)—,

—O—;

S(O)_p, wherein p is 0, 1, or 2;

C(═O);

C(═S);

CHR₂;

—C(═O)CH(R²)N(R^d1)—; and

—C(═O)CH(R²)CH₂N(R^d1)—.