# US 2018/0022752 A1 · Fused-ring compounds, pharmaceutical composition and uses thereof

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- Number: US 2018/0022752 A1
- Document ID: US20180022752A1
- Status: Published application
- Kind: A1
- Application number: 15/548,664
- Filed: 2016-02-03
- Published: 2018-01-25
- Earliest claimed: 2015-02-16
- Assignees: Shanghai De Novo Pharmatech Co., Ltd.
- Applicants: Shanghai De Novo Pharmatech Co., Ltd.
- Inventors: Qun LI; Daxin GAO
- Web page: https://patentgrep.com/patent/US20180022752A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/4245: Oxadiazoles
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/14: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This disclosure is related to a fused-ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the fused ring compound of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in modulating activity of indoleamine 2, 3-dioxygenase (IDO) and/or tryptophan 2, 3-dioxygenase (TDO). This disclosure further provides methods of treating IDO and/or TDO-associated diseases, including cancer, viral infection and autoimmune diseases.

## Claims

### Claim at position 1

1-63. (canceled)

### Claim 64

A compound of formula (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof;
Wherein,
n is 1, 2 or 3; t is 1 or 2; U is N, C, or CR4, bond α is a single or double bond;
when U is N or CR4, bond α is a single bond; when U is C, bond α is a double bond;
A ring is 5-membered heteroaromatic ring;
Z, Z1, Z2, Z3, Z4 are independently N or C, and Z3 and Z4 are not N at the same time;
B ring is benzene or a 5- or 6-membered heteroaromatic ring;
When bond α is a single bond, A1 is —(CR9R9a)m— or —C2-4 alkenyl-;
When bond α is a double bond, A1 is —CR9(CR9R9a)m—;
R9 is independently hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclolalkyl, substituted or unsubstituted alkoxy, wherein the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, or substituted alkoxy is alkyl, cycloalkyl, heterocycloalkyl, or alkoxy substituted by one or more substituent(s) at any position independently selected from halogen, hydroxyl, alkyl, heterocycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl, —SR6, —NR6R6a, —S(O)2NR6R6a, —NR8C(O)NR6R6a, —NR6C(O)R6a, —NR6S(O)2R6a, —C(O)R6, —S(O)0-2R6, —C(O)OR6, —C(O)NR6R6a, —(CH2)rOH, and —(CH2)rNR6R6a;
R9a is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl; or R9 and R9a together with the carbon atom to which they are attached form a 3- to 8-membered mono-cycloalkyl ring, wherein the substituted alkyl is alkyl substituted by one or more substituent(s) at any position independently selected from hydroxyl, halogen, and C3-6 cycloalkyl;
A2 is —C(═R7)(CR5R5a)m—, —(CR5R5a)m—, —(C═R7)O—, —(CR5R5a)mO—, or —S(O)0-2(CR5R5a)m—;
R5 and R5a are independently hydrogen, hydroxyl, halogen, alkyl, amino, —SR6, —OR6, —NR6R6a, —NR6S(O)2R6a, —S(O)2NR6R6a, —(CH2)rS(O)0-2CH3, —OS(O)3H, —OP(O)(O—R6)2, —OC(O)R6, —OC(O)NR6R6a, —C(O)NR6R6a, —(CH2)rC(O)OH, —(CH2)rOH, —(CH2)rC(O)NR6R6a, or —(CH2)rNR6R6a;
R1 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkylthiol, haloalkyl, haloalkoxy, amino, C2-6alkynyl, C2-6alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —SH, —CN, —NO2, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R6a, —C(O)OR6, —C(O)R6, —C(O)NR6R6a, —NR6R6a, —NR6C(O)R6a, —NR6C(O)OR6a, —NR6C(O)NR6R6a, —(CH2)rNR6R6a, —NR6S(O)2R6a, —S(O)0-2R6, or —S(O)2NR6R6a;
R2 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkylthiol, haloalkyl, haloalkoxy, amino, C2-6 alkynyl, C2-6 alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —SH, —CN, —NO2, or —NR6R6a;
R3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bridged tricycloalkyl, or substituted or unsubstituted bridged heterocycloalkyl; provided that when U is C or CR4 and B ring is benzene, R3 is substituted or unsubstituted bridged tricycloalkyl, or substituted or unsubstituted bridged heterocycloalkyl, wherein the substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted bridged tricycloalkyl, or substituted bridged heterocycloalkyl is substituted by one or more R10;
R4 is hydrogen, deuterium, halogen, —CN, —C(O)OH, tetrazole, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, wherein the substituted alkyl, substituted alkoxy is substituted at any position by one or more R12 which is independently selected from halogen, hydroxyl, alkyl, bridged tricycloalkyl, alkoxy, aryl, heteroaryl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, —SR6, —NR6R6a, —S(O)2NR6R6a, —NR6C(O)NR6R6a, —C(O)R6, —S(O)0-2R6, —C(O)OR6, —(CH2)rOH, and —(CH2)rNR6R6a, further wherein the substituted cycloalkyl, or substituted heterocycloalkyl is substituted by one or more of substituent(s) independently selected from hydroxyl, amino, and halogen;
R10 is independently -L-C(R8)═R10a, —NO2, —CN, —OH, —NH2, —SH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted bridged tricycloalkyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C2-6 alkenyl, —C2-6 alkynyl-R8b, -L-R8, —O-L-R8, —S(O)0-2-L-R8, —N(R8)-L-R8b, -L-OR8b, -L-OC(O)R8b, -L-OC(O)NR8R8b, -L-OC(O)OR8b, -L-OP(O)(O—R8)2, -L-B(O—R8)2, -L-OS(O)2(OH), -L-OS(O)1-2R8b, -L-S(O)1-2OR8b, -L-S(O)2NR8R8b, -L-S(O)0-2R8b, -L-S(O)2N(R8)C(O)NR8R8b, -L-C(O)OR8b, -L-C(O)R8b, -L-C(O)N(OH)R8b, -L-C(═R7)NR8R8b, -L-NR8R8b, -L-N(R8)C(O)OR8b, -L-N(R8)C(═R7)R8b, -L-N(R8)C(O)N(R8)S(O)2R8b, -L-N(R8)OR8b, -L-N(R8)C(═R7)NR8R8b, -L-N(R8)S(O)1-2R8b, -L-N(R8)S(O)1-2NR8R8b, or R8 and R8b together with the nitrogen atom to which they are attached, form a 3- to 8-membered mono-heterocycloalkyl ring; wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkylalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, substituted heteroarylalkyl, substituted bridged tricycloalkyl, substituted C2-6 alkenyl, or substituted C2-6 alkynyl, is substituted by 1 to 3 R13 at any position;
R13 is —OH, —SH, —CN, —NO2, —NH2, halogen, alkylthiol, —C(═R7)NR6R6a, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R6a, —C(O)OR6, —C(O)R6, —C(O)NR6R6a, —NR6R6a, —NR6C(O)R6a, —NR6C(═R7)R6a, —NR6C(O)OR6a, —NR6C(O)NR6R6a, —NR6C(═R7)NR6R6a, —(CH2)rNR6R6a, —NR6S(O)2R6a, —NR6S(O)2NR6R6a, —S(O)0-2R6, —S(O)2NR6R6a, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; wherein the substituted alkyl, substituted alkoxy, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted at any position by 1 to 3 substituent(s) independently selected from C1-3 alkyl, halogen, C1-3 alkoxy, halo-C1-3 alkoxy, hydroxyl, and amino;
is selected from ═O, ═S, ═N(R8b), ═N(OR8b), ═C(R8b)2, ═C(R8b)(OR8b), and ═C(R8b)(NHR8b);
L is a bond or L1, wherein L1 is —(CR8R8a)r; or R8 and R8a together with the carbon atom to which they are attached, form a 3- to 8-membered mono-cycloalkyl ring;
R8 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, one-end modified or unmodified polyethylene glycol, monosaccharide, disaccharide, amino acid, peptide with 3-20 amino acid residues, or
R8a is selected from hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl;
R8b is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, -L1-R8, -L1-OR8, -L1-N(R8)2, -L1-C(O)OR8, -L1-OC(O)R8, -L1-C(O)N(R8)2, -L1-N(R8)C(O)R8, -L1-N(R8)C(O)N(R8)2, -L1-N(R8)C(S)N(R8)2, -L1-OS(O)1-2R8, -L1-S(O)1-2OR8, -L1-S(O)0-2R8, -L1-N(R8)S(O)2N(R8)2, -L1-S(O)2N(R8)2, -L1-N(R8)S(O)2R8, -L1-N(R8)C(O)N(R8)S(O)2R8, and -L1-OP(O)(O—R8)2;
further wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkylalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, or substituted heteroarylalkyl in R8, R8a or R8b is substituted at any position by 1 to 3 R14 group independently selected from —OH, —SH, —CN, —NO2, —NH2, halogen, alkylthiol, —C(═R7)NR6R6a, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R6a, —C(O)OR6, —C(O)R6, —C(O)NR6R6a, —NR6R6a, —NR6C(O)R6a, —NR6C(═R7)R6a, —NR6C(O)OR6a, —NR6C(O)NR6R6a, —NR6C(═R7)NR6R6a, —(CH2)rNR6R6a, —NR6S(O)2R6a, —NR6S(O)2NR6R6a, —S(O)0-2R6, —S(O)2NR6R6a, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted heteroaryl, wherein the substituted alkyl, substituted alkoxy, substituted C2-6 alkenyl, substituted C2-6 alkynyl, or substituted aryl, substituted heteroaryl, substituted cycloalkyl, or substituted heterocycloalkyl in R14 group is substituted at any position by 1 to 3 substituent(s) independently selected from C1-3 alkyl, halogen, C1-3 alkoxy, halo-C1-3 alkoxy, hydroxyl, and amino;
is independently ═O, ═S, ═N(R6), or ═N(OR6);
R6 and R6a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, or R6 and R6a together with the nitrogen atom to which they are attached, form a 3- to 8-membered mono-heterocycloalkyl ring;
r is an integer ranging from 1 to 8; and
m is 0, 1, 2, or 3.

### Claim 65 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R8b is hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C3-8 cycloalkyl-C1-4 alkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted or unsubstituted C6-10 aryl-C1-4alkyl, substituted or unsubstituted 5- to 6-membered heteroaryl-C1-4 alkyl, -L1-R8, -L1-OR8, -L1-N(R8)2, -L1-C(O)OR8, -L1-OC(O)R8, -L1-C(O)N(R8)2, -L1-N(R8)C(O)R8, -L1-N(R8)C(O)N(R8)2, -L1-N(R8)C(S)N(R8)2, -L1-OS(O)1-2R8, -L1-S(O)1-2OR8, -L1-S(O)0-2R8, -L1-N(R8)S(O)2N(R8)2, -L1-S(O)2N(R8)2, -L1-N(R8)S(O)2R8, -L1-N(R8)C(O)N(R8)S(O)2R8, or -L1-OP(O)(O—R8)2; and further wherein substituted C1-4 alkyl, substituted C1-4 alkoxy, substituted C3-8 cycloalkyl, substituted 5- to 8-membered heterocycloalkyl, substituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, substituted C3-8 cycloalkyl-C1-4 alkyl, substituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted C6-10 aryl-C1-4 alkyl, or substituted 5- to 6-membered heteroaryl-C1-4 alkyl for R8b is substituted at any position by 1 to 3 R14.

### Claim 66 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R8 is hydrogen, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C3-8 cycloalkyl-C1-4 alkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted or unsubstituted C6-10 aryl C1-4 alkyl, substituted or unsubstituted 5- to 6-membered heteroaryl-C1-4 alkyl, or
and further wherein the substituted C1-4 alkyl, substituted C1-4alkoxy, substituted C3-8 cycloalkyl, substituted 5- to 8-membered heterocycloalkyl, substituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, substituted C3-8 cycloalkyl-C1-4 alkyl, substituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted C6-10 aryl C1-4alkyl, or substituted 5- to 6-membered heteroaryl-C1-4 alkyl for R8 is substituted at any position by 1 to 3 R14.

### Claim 67 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R8a is hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4alkoxy, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C3-8 cycloalkyl-C1-4 alkyl, substituted or unsubstituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted or unsubstituted C6-10 aryl C1-4 alkyl, substituted or unsubstituted 5- to 6-membered heteroaryl-C1-4 alkyl, and wherein the substituted C1-4 alkyl, substituted C1-4 alkoxy, substituted C3-8 cycloalkyl, substituted 5- to 8-membered heterocycloalkyl, substituted C6-10 aryl, substituted 5- to 6-membered heteroaryl, substituted C3-8 cycloalkyl-C1-4 alkyl, substituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted C6-10 aryl C1-4 alkyl, substituted 5- to 6-membered heteroaryl-C1-4alkyl for R8a is substituted at any position by 1 to 3 R14.

### Claim 68 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein Z, Z1, Z2, Z3, and Z4 in A ring are selected from (1) Z1 and Z4 are N; Z, Z2, Z3 are C; (2) Z1 and Z3 are N; Z, Z2 and Z4 are C; (3) Z, Z1 and Z4 are N; Z2 and Z3 are C; (4) Z1, Z2 and Z3 are N; Z and Z4 are C; (5) Z1, Z2 and Z4 are N; Z and Z3 are C; (6) Z, Z1 are Z3 are N; Z2 and Z4 are C; and (7) Z, Z1 and Z2 are N; Z3 and Z4 are C.

### Claim 69 (depends on 64, 68)

The compound or the pharmaceutically acceptable salt thereof of claim 68, wherein U is CR4, and Z, Z1, Z2, Z3, and Z4 in A ring are selected from 1) Z1 and Z4 are N; Z, Z2 and Z3 are C; and 2) Z1 and Z3 are N; Z, Z2 and Z4 are C, and further wherein R4 is as defined in claim 64,
or U is N, and A ring is a ring wherein Z1 and Z3 are N, and Z, Z2 and Z4 are C.

### Claim 70 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R4 is hydrogen, fluorine, hydroxyl, C1-4alkyl, or C1-4alkoxy,
or U is CH, bond α is a single bond,
or B ring is benzene, thiophene, pyridine, or pyrimidine,
or R9 is hydrogen, halogen, substituted or unsubstituted C1-4 alkyl, or substituted or unsubstituted C1-4 alkoxy, and wherein the substituted C1-4 alkyl or substituted C1-4 alkoxy is a C1-4 alkyl or C1-4 alkoxy substituted by one or more substituent(s) at any position independently selected from halogen, hydroxyl, alkyl, heterocycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl, —SR6, —NR6R6a, —S(O)2NR6R6a, —NR6C(O)NR6R6a, —NR6C(O)R6a, —NR6S(O)2R6a, —C(O)R6, —S(O)0-2R6, —C(O)OR6, —C(O)NR6R6a, —(CH2)rOH, and —(CH2)rNR6R6a; further wherein R6, R6a, and r are as defined in claim 64; R9a is hydrogen, deuterium, halogen, or substituted or unsubstituted C1-4 alkyl, wherein the substituted C1-4 alkyl is alkyl substituted by one or more substituent(s) at any position independently selected from hydroxyl, halogen, and C3-6cycloalkyl,
or R5 or R5a in A2 is hydrogen, —SR6, —OR6, —NR6R6a, —NHSO2R6, —NR6SO2R6a, —OP(O)(O—R6)2, —OC(O)R6.

### Claim 71 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein A1 is —CH2—, —CHF—, —CF2—, —CHCH3— or —C(CH3)2—,
or A2 is —CHF—, —CH(CN)—, —CH(COOH)—, —CH(OH)—, —CH(OPO3H)—, —C(CH3)(OH)—,
or R1 is —OH, —SH, —CN, hydrogen, halogen, amino, C1-3 alkoxy, C1-3 alkylthiol, C1-3 alkyl, halo-C1-3 alkyl or halo-C1-3 alkoxy,
or R2 is —OH, —SH, —NH2, hydrogen, halogen, C1-3 alkoxy, C1-3 alkylthiol, C1-3 alkyl, or halo-C1-3 alkyl.

### Claim 72 (depends on 64, 65)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R3 is substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted bridged C7-10 tricycloalkyl, or substituted or unsubstituted bridged 7- to 10-membered heterocycloalkyl, and further wherein the substituted C1-3 alkyl, substituted C3-12 cycloalkyl, substituted 3- to 12-membered heterocycloalkyl, substituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, substituted bridged C7-10 tricycloalkyl, or substituted bridged 7- to 10-membered heterocycloalkyl is substituted by one or more R10 which is as defined in claim 64,
or R3 is substituted or unsubstituted bicyclo[2.2.1]heptyl, substituted or unsubstituted (1R, 5S)-bicyclo[3.2.1]octyl, or substituted or unsubstituted decahydronaphthalenyl, and wherein the substituted bicyclo[2.2.1]heptyl, substituted (1R, 5S)-bicyclo[3.2.1]octyl, or substituted decahydronaphthalenyl is substituted by one or more R10 which is as defined in claim 64,
or R3 is substituted or unsubstituted 2-azabicyclo[2.2.1]heptyl, substituted or unsubstituted 2-oxabicyclo[2.2.1]heptyl, substituted or unsubstituted 2,5-diazabicyclo[2.2.1] heptyl, substituted or unsubstituted (1S, 5S)-9-oxabicyclo[3.3.1]nonyl, substituted or unsubstituted (1R, 5S)-8-oxabicyclo[3.2.1]octyl, substituted or unsubstituted (1R, 5S)-3-oxabicyclo[3.2.1]octyl, substituted or unsubstituted (1R, 5S)-3-azabicyclo[3.2.1]octyl, substituted or unsubstituted (1R, 5S)-8-azabicyclo[3.2.1]octyl, substituted or unsubstituted quinuclidinyl, substituted or unsubstituted 2-aza-bicyclo[2.2.2]octyl, or substituted or unsubstituted 2-azaadamantanyl, and wherein the substituted 2-azabicyclo[2.2.1]heptyl, substituted 2-oxabicyclo[2.2.1]heptyl, substituted 2,5-diazabicyclo[2.2.1]heptyl, substituted (1S, 5S)-9-oxabicyclo[3.3.1]nonyl, substituted (1R, 5S)-8-oxabicyclo[3.2.1]octyl, substituted (1R, 5S)-3-oxabicyclo[3.2.1]octyl, substituted (1R, 5S)-3-azabicyclo[3.2.1]octyl, substituted (1R, 5S)-8-azabicyclo[3.2.1]octyl, substituted quinuclidinyl, substituted 2-aza-bicyclo[2.2.2] octyl, or substituted 2-azaadamantanyl is substituted by one or more R10 which is as defined in claim 64,
or R3 is substituted or unsubstituted adamantanyl, and wherein the substituted adamantanyl is substituted by one or more R10 which is as defined in claim 64,
or R10 is independently —NO2, —CN, —OH, —NH2, —SH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R8)-L-R8b, -L-R8, —O-L-R8, -L-C(O)R8b, -L-C(═R7)NR8R8b, -L-S(O)2R8b, -L-NR8R8b, -L-N(R8)C(═R7)R8b, -L-N(R8)C(═R7)NR8R8b and -L-N(R8)S(O)2R8b, wherein the substituted alkyl, substituted alkoxy, substituted aryl, substituted heteroaryl is substituted by 1 to 3 R13, and further wherein R7, L, and R13 are the same as defined in claim 64, and R8, R8b are as defined in claim 64, 65, or 66.

### Claim 73 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein the substituted or unsubstituted alkyl for R10 is substituted or unsubstituted C1-4 alkyl, the substituted or unsubstituted alkoxy for R10 is substituted or unsubstituted C1-4 alkoxy, the substituted or unsubstituted aryl for R10 is substituted or unsubstituted C6-10 aryl, the substituted or unsubstituted heteroaryl for R10 is substituted or unsubstituted 5- to 10-membered heteroaryl, the substituted or unsubstituted cycloalkyl for R10 is substituted or unsubstituted C3-8 cycloalkyl, the substituted or unsubstituted heterocycloalkyl for R10 is substituted or unsubstituted 5- to 8-membered heterocycloalkyl, the substituted or unsubstituted cycloalkylalkyl for R10 is substituted or unsubstituted C3-8 cycloalkyl-C1-4 alkyl, the substituted or unsubstituted heterocycloalkylalkyl for R10 is substituted or unsubstituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, the substituted or unsubstituted arylalkyl for R10 is substituted or unsubstituted C6-10 aryl-C1-4alkyl, the substituted or unsubstituted heteroarylalkyl for R10 is substituted or unsubstituted 5- to 10-membered heteroaryl-C1-4 alkyl, or the substituted or unsubstituted bridged tricycloalkyl for R10 is substituted or unsubstituted adamantanyl, and wherein the substituted C1-4 alkyl, substituted C1-4 alkoxy, substituted C6-10 aryl, substituted 5- to 10-membered heteroaryl, substituted C3-8 cycloalkyl, substituted 5- to 8-membered heterocycloalkyl, substituted C3-8 cycloalkyl-C1-4 alkyl, substituted 5- to 8-membered heterocycloalkyl-C1-4 alkyl, substituted C6-10 aryl-C1-4alkyl, substituted 5- to 10-membered heteroaryl-C1-4 alkyl, or substituted adamantanyl is substituted by 1 to 3 R13.

### Claim 74 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R13 is independently F, Cl, Br, —OH, —SH, —CN, —NO2, —NH2, C1-4alkylthiol, C3-8cycloalkyl, —C(O)NR6R6a, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R6a, —C(O)OR6, —C(O)R6, —C(O)NR6R6a, —NR6R6a, —NR6C(O)R6a, —NR6C(O)R6a, —NR6C(O)OR6a, —NR6C(O)NR6R6a, —NR6C(O)NR6R6a, —NR6S(O)2R6a, —NR6S(O)2NR6R6a, —S(O)0-2R6, —S(O)2NR6R6a, —(CH2)rNR6R6a, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted 5- to 8-membered heterocycloalkyl;
further wherein the substituted C1-4 alkyl, substituted C1-4 alkoxy, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-8 cycloalkyl, or substituted 5- to 8-membered heterocycloalkyl is substituted at any position by 1 to 3 substituent(s) independently selected from C1-3 alkyl, halogen, C1-3 alkoxy, halo-C1-3 alkoxy hydroxyl, and amino.

### Claim 75 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R14 is independently F, Cl, Br, —OH, —SH, —CN, —NO2, —NH2, C1-4alkylthiol, C3-8 cycloalkyl, —C(O)NR6R6a, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R6a, —C(O)OR6, —C(O)R6, —C(O)NR6R6a, —NR6R6a, —NR6C(O)R6a, —NR6C(O)R6a, —NR6C(O)OR6a, —NR6C(O)NR6R6a, —NR6C(O)NR6R6a, —(CH2)rNR6R6a, —NR6S(O)2R6a, —NR6S(O)2NR6R6a, —S(O)0-2R6, —S(O)2NR6R6a, substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C1-4 alkoxy, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted C3-8 cycloalkyl, or substituted or unsubstituted 5- to 8-membered heterocycloalkyl;
and wherein the substituted C1-4 alkyl, substituted C1-4 alkoxy, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted phenyl, substituted 5- to 6-membered heteroaryl, substituted C3-8 cycloalkyl, or substituted 5- to 8-membered heterocycloalkyl is substituted at any position by 1 to 3 substituent(s) independently selected from C1-3 alkyl, halogen, C1-3 alkoxy, halo-C1-3 alkoxy hydroxyl, and amino.

### Claim 76 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein R6 and R6a are independently hydrogen, C1-4 alkyl, halo-C1-4 alkyl, C3-8 cycloalkyl, 5- to 8-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, 5- to 8-membered heterocycloalkyl-C1-4 alkyl, C3-8 cycloalkyl-C1-4 alkyl, C6-10 aryl-C1-4 alkyl, or 5- to 6-membered heteroaryl-C1-4 alkyl, or R6 and R6a together with the nitrogen atom to which they are attached, form a 3- to 8-membered mono-heterocycloalkyl ring.

### Claim 77 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein
is ═O, ═S, ═N—OH, or ═NH,
or L1 is —CH2—, —CH2CH2—, —CH2CH2CH2— or —C(CH3)2—,
or R10 is hydrogen, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, isopropoxy, cyclohexyloxy, phenoxy, benzyloxy, phenyl, pyridinyl, pyrimidinyl, tetrazole, carboxyl, —OH, —NO2, —NH2, —NHC(O)CH3, —C(O)NH2, —CN, —OCF3, —CF3, —CH2OH, —CH2NH2, —OP(O)(OH)2,
or R10a is
or R3 is

### Claim 78 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is
1) a compound of formula (IA) or a pharmaceutically acceptable salt thereof,
2) a compound of formula (IB) or a pharmaceutically acceptable salt thereof,
3) a compound of formula (IC) or a pharmaceutically acceptable salt thereof,
4) a compound of formula (ID) or a pharmaceutically acceptable salt thereof,
5) a compound of formula (IA-1) or a pharmaceutically acceptable salt thereof,
6) a compound of formula (IB-1) or a pharmaceutically acceptable salt thereof,
7) a compound of formula (IE) or a pharmaceutically acceptable salt thereof,
8) a compound of formula (IF) or a pharmaceutically acceptable salt thereof,
9) a compound of formula (IF-1) or a pharmaceutically acceptable salt thereof,
10) a compound of formula (IG) or a pharmaceutically acceptable salt thereof,
11) a compound of formula (IH) or a pharmaceutically acceptable salt thereof,
12) a compound of formula (IJ) or a pharmaceutically acceptable salt thereof, or
13) a compound of formula (IK) or a pharmaceutically acceptable salt thereof,
Wherein,
in formula (IA), (IB), (IC) and (ID), Y, Y1, X, and X1 are independently C or N; p is 1 or 2; Z, Z1, Z2, Z3, Z4, R1, R2, U, bond α, A1, A2, R10, n and t are the same as described in claim 64,
in formula (IA-1) and (IB-1), X and X1 are independently C or N; p is 1 or 2, R1, R2, R4, R10, A1, A2, and n are the same as defined in claim 64,
in formula (IE) and (IF), X and X1 are independently C or N; R1, R2, R4, R10, n, A1, and A2 are the same as defined in claim 64, the stereoisomeric configurations of the single bond labeled with are cis, trans, or a mixture of cis/trans,
in formula (IF-1), R1 is hydrogen or halogen; R10 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R8, wherein substituted alkyl, aryl, and heteroaryl are substituted by 1, 2, or 3 R13, further wherein R8, and R13 are the same as defined in claim 64; A1 and A2 are the same as defined in claim 64; the stereoisomeric configurations of the single bond labeled with are cis, trans, or a mixture of cis/trans,
in formula (IG) and (IH), X, X1, Y, and Y1 are independently C or N; R1, R4, R10, n, A1, and A2 are the same as defined in claim 64,
in formula (IJ) and (IK), Y, Y1, X, and X1 are independently C or N; Z, Z1, Z2, Z3, Z4, R1, R2, R3, R5, t, and n are the same as defined in claim 64; the stereoisomeric configurations of carbon atoms labeled with * are respectively (S, S), (S, R), (R, S), (R, R).

### Claim 79 (depends on 78)

The compound or the pharmaceutically acceptable salt thereof of claim 78, wherein Z and Z2 are C, Z1 is N, and one of Z3 and Z4 is N and the other is C in formula (IA), (IB), (IC) and (ID),
or bond α is a single bond, U is CR4 in formulae (IA), (IB), (IC) and (ID), or R4 in formulae (IA-1), (IB-1), (IE), (IF), (IG), and (IH) is hydrogen, hydroxyl, fluorine, or methyl,
or X and X1 in formulae (IA), (IA-1), (IB), (IB-1), (IE), and (IF) are C; or Y and Y1 in formulae (IC) and (ID) are C,
or one of X and X1 in formulae (IA), (IA-1), (IB), (IB-1), (IE), and (IF) is N and the other is C,
or R1 in formulae (IA), (IA-1), (IB), (IB-1), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), and (IK) is —OH, —SH, —CN, hydrogen, halogen, amino, C1-3 alkoxy, C1-3 alkylthiol, C1-3 alkyl, halo-C1-3 alkyl, or halo-C1-3 alkoxy, and n is 2 in in formulae (IG), (IH), (IJ), and (IK), or R2 in formulae (IA), (IA-1), (IB), (IB-1), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), and (IK) is —OH, —SH, —NH2, hydrogen, halogen, C1-3 alkoxy, C1-3 alkylthiol, C1-3 alkyl, or halo-C1-3 alkyl, and t is 2 in in formulae (IG), (IH), (IJ), and (IK), or A1 in formulae (IA), (IA-1), (IB), (IB-1), (IC), (ID), (IE), (IF), (IF-1) (IG), and (IH) is —CH2—, —CHF—, —CF2—, —CHCH3— or —C(CH3)2—,
or A2 in formulae (IA), (IA-1), (IB), (IB-1), (IC), (ID), (IE), (IF), (IF-1), (IG), and (IH) is —CHF—, —CH(CN)—, —CH(COOH)—,
or Y, Y1, X, and X1 are C in formulae (IG), (IH), (IJ), and (IK),
or Z and Z2 are C, Z1 is N, and one of Z3 and Z4 is N and the other is C in formulae (IJ), and (IK),
or R5 in formulae (IJ), and (IK) is independently H, OH, alkyl, —OR6, and —OP(O)(O—R6)2, wherein R6 is H or alkyl,
or R3 in formulae (IJ), and (IK) is unsubstituted adamantanyl or adamantanyl substituted with 1 or 2 R10,
or R3 in formulae (IJ), and (IK) is unsubstituted 2-azaadamantanyl or 2-azaadamantanyl substituted with 1 or 2 R10,
or R10 in formulae (IA), (IA-1), (IB), (IB-1), (IC), (ID), (IE), (IF), (IF-1), (IG), and (IH) is independently —NO2, —CN, —OH, —NH2, —SH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R8)-L-R8b, -L-R8, —O-L-R8, -L-C(O)R8b, -L-C(═R7)NR8R8b, -L-S(O)2R8b, -L-NR8R8b, -L-N(R8)C(═R7)R8b, -L-N(R8)C(═R7)NR8R8b and -L-N(R8)S(O)2R8b, wherein substituted alkyl, substituted alkoxy, substituted aryl, and substituted heteroaryl are substituted by 1, 2, or 3 R13.

### Claim 80 (depends on 64)

The compound or the pharmaceutically acceptable salt thereof of claim 64, wherein the compound is

### Claim 81 (depends on 64)

A pharmaceutical composition comprising 1) the compound and/or the pharmaceutically acceptable salt thereof of claim 64, and 2) a pharmaceutically acceptable excipient.

### Claim 82 (depends on 64)

A method for treating a disease treatable by inhibition of IDO1 and/or TDO2 in a mammal comprising administering to the mammal in recognized need of such treatment, a therapeutically effective amount of the compound and/or the pharmaceutically acceptable salt thereof of claim 64.

### Claim 83 (depends on 81)

A method for treating a disease treatable by inhibition of IDO1 and/or TDO2 in a mammal comprising administering to the mammal in recognized need of such treatment, a therapeutically effective amount of the pharmaceutical composition of claim 81.

### Claim 84 (depends on 64, 82)

The method of claim 82, further comprising administering to the mammal in recognized need of such treatment an additional agent prior to, concurrent with, or subsequent to the compound of claim 64, the additional agent is selected from anti-microtubule agents, alkylating agents, topoisomerase I/II inhibitors, platinum coordination complexes, antimetabolites, immunotherapeutic agents, signal transduction pathway inhibitors, and angiogenesis inhibitors,
or the disease treatable by inhibition of IDO1 and/or TDO2 is cancer, viral infection, or autoimmune disease,
or the mammal is human.

### Claim 85 (depends on 81, 83)

The method of claim 83, further comprising administering to the mammal in recognized need of such treatment an additional agent prior to, concurrent with, or subsequent to the pharmaceutical composition of claim 81, the additional agent is selected from anti-microtubule agents, alkylating agents, topoisomerase I/II inhibitors, platinum coordination complexes, antimetabolites, immunotherapeutic agents, signal transduction pathway inhibitors, and angiogenesis inhibitors,
or the disease treatable by inhibition of IDO1 and/or TDO2 is cancer, viral infection, or autoimmune disease,
or the mammal is human.