Matriptase 2 inhibitors and uses thereof

A compound of Formula IV:

• or a pharmaceutically acceptable salt thereof, wherein
• L1 is a bond, or an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally and independently replaced by —C(O)— or —O—;
• R1 is an optionally substituted ring selected from phenyl, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aromatic carbocyclic ring, and an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• L2 is an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are independently replaced by —NR—C(O)—, —C(O)—NR—, —C(O)—, —C(O)—O—, —O—C(O)—, —NR—S(O)2—, —S(O)2—NR—, or -Cy-,
• -Cy- is an optionally substituted bivalent 4-6 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R2 is an optionally substituted ring selected from a 4-7 membered monocyclic carbocyclic ring, a 4-7 membered monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic carbocyclic ring, a 7-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aromatic ring, an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and adamantyl;
• R3 is H, —OH, halogen, —CN, —C(O) H, —NH2, —NO2, —COOH, —CONH2, —NH—C(O)—O—C1-6aliphatic, C1-6aliphatic, or —C(O)—C1-6aliphatic, wherein the C1-6aliphatic is optionally substituted;
• L3 is an optionally substituted bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain, wherein 1, 2, or 3 methylene units of the hydrocarbon chain are optionally replaced by —CO—;
• R4 is —NHR, —C(N—R)—NHR, —NH—C(N—R)—NHR, or —OH;
• and
• each R is independently H, —OH, —OC1-8alkyl, —C(O)—C1-8alkyl, —C(O)—OC1-8alkyl, —O-(4-7 membered monocyclic carbocyclyl), —C(O)-(4-7 membered monocyclic carbocyclyl), —C(O)—O-(4-7 membered monocyclic carbocyclyl), phenyl, —O-phenyl, —C(O)-phenyl, —C(O)—O-phenyl, 8-10 membered bicyclic aryl, —O-(8-10 membered bicyclic aryl), —C(O)-(8-10 membered bicyclic aryl), or —C(O)—O-(8-10 membered bicyclic aryl), wherein each of the C1-8alkyl, 4-7 membered monocyclic carbocyclyl, phenyl, and 8-10 membered bicyclic aryl is optionally and independently substituted.