Bridged Cyclic 5-Amino-6,8-Dihydro-1H-Furo[3,4-D]Pyrrolo[3,2-B]Pyridine-2-Carboxamide Compounds, Compositions Thereof, and Methods of Treatment Therewith

CROSS-REFERENCE TO RELATED APPLICATIONS

FIELD

BACKGROUND

SUMMARY

• • [0011] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein:
  • [0012] L is a single bond or —C(R⁸R⁹)—;
  • [0013] n1 is 0, 1, 2, 3 or 4;
  • [0014] X¹ is CR^2h or N;
  • [0015] X² is C(R²ⁱR^2j), O, or NR^2k, provided that X² is C(R²ⁱR^2j) when X¹ is N;
  • [0016] X³ is N or CH;
  • [0017] R¹ is each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, substituted or unsubstituted —C₆-C₁₂aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, —OR^1a, —SO₂R^1a, —SO₂NR^1aR^1b, —COR^1a, —CO₂R^1a, —CONR^1aR^1b, —NR^1aR^1b, —NR^1aCOR^1b, —NR^1aCO₂R^1b, —NR^1aSO₂R^1b, or —CN;
  • [0018] R^1a and R^1b are each independently selected from hydrogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, substituted or unsubstituted —C₆-C₁₂aryl and substituted or unsubstituted 5- to 12-membered heteroaryl;
  • [0019] R^2a, R^2b, R^2c, R^2d, R^2e, R^2f, R^2g, R^2h, R²ⁱ and R^2j are each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocyclyl; or
  • [0020] (R^2b and R^2c), (R^2d and R^2e), (R^2f and R^2g) or (R²ⁱ and R^2j) taking together with the atom to which they are attached, form a 3- to 8-membered unsaturated or saturated substituted or unsubstituted ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • [0021] R^2k are each independently selected from hydrogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl and substituted or unsubstituted 3- to 8-membered heterocyclyl;
  • [0022] R³ is selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, —CN, —OH, or —NH₂;
  • [0023] R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl or substituted or unsubstituted —C₃-C₈cycloalkyl.

DETAILED DESCRIPTION

Definitions

and Formula (VIc″):

Compounds

• • [0065] or a hydrate thereof, or a solvate thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, wherein:
  • [0066] L is a single bond or —C(R⁸R⁹)—;
  • [0067] n1 is 0, 1, 2, 3 or 4;
  • [0068] X¹ is CR^2h or N;
  • [0069] X² is C(R²ⁱR^2j), O, NR^2k or; provided that X² is C(R²ⁱR^2j) when X¹ is N;
  • [0070] X³ is N or CH;
  • [0071] R¹ is each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, substituted or unsubstituted —C₆-C₁₂aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, —OR^1a, —SO₂R^1a, —SO₂NR^1aR^1b, —COR^1a, —CO₂R^1a, —CONR^1aR^1b, —NR^1aR^1b, —NR^1aCOR^1b, —NR^1aCO₂R^1b, —NR^1aSO₂R^1b, and —CN;
  • [0072] R^1a and R^1b are each independently selected from hydrogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, substituted or unsubstituted —C₆-C₁₂aryl, and substituted or unsubstituted 5- to 12-membered heteroaryl;
  • [0073] R^2a, R^2b, R^2c, R^2d, R^2e, R^2f, R^2g, R^2h, R²ⁱ and R^2j are each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, and substituted or unsubstituted 3- to 8-membered heterocyclyl; or
  • [0074] (R^2b and R^2c), (R^2d and R^2e), (R^2f and R^2g) or (R²ⁱ and R^2j) taking together with the atom to which they are attached, form a 3- to 8-membered unsaturated or saturated substituted or unsubstituted ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • [0075] R^2k are each independently selected from hydrogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, and substituted or unsubstituted 3- to 8-membered heterocyclyl;
  • [0076] R³ is selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, substituted or unsubstituted —C_2-8alkenyl, substituted or unsubstituted —C_2-8alkynyl, substituted or unsubstituted —C₃-C₈cycloalkyl, —CN, —OH, and —NH₂;
  • [0077] R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, halogen, substituted or unsubstituted —C_1-8alkyl, and substituted or unsubstituted —C₃-C₈cycloalkyl.
    Aspect 2. The compound, or the hydrate, or the solvate, or the N-oxide, or the pharmaceutically acceptable salt, or the stereoisomer, or the tautomer, or the deuterated analog of Aspect 1, wherein:
  • [0078] L is a single bond or —C(R⁸R⁹)—;
  • [0079] n1 is 0, 1, 2, 3 or 4;
  • [0080] X¹ is CR^2h or N;
  • [0081] X² is C(R²ⁱR^2j), O, NR^2k or; provided that X² is C(R²ⁱR^2j)₂ when X¹ is N;
  • [0082] X³ is N or CH;
  • [0083] R¹ is each independently selected from hydrogen, halogen, —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —OR^1a, —SO₂R^1a, —SO₂NR^1aR^1b, —COR^1a, —CO₂R^1a, —CONR^1aR^1b, —NR^1aR^1b, —NR^1aCOR^1b, —NR^1aCO₂R^1b, —NR^1aSO₂R^1b, and —CN, wherein each of said —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^1c;
  • [0084] R^1a and R^1b are each independently selected from hydrogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent Rid;
  • [0085] R^1c and R^1d are each independently hydrogen, halogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —OR^1e, —SO₂R^1e, —SO₂NR^1eR^1f, —COR^1e, —CO₂R^1e, —CONR^1eR^1f, —NR^1eR^1f, —NR^1eCOR^1f, —NR^1eCOR₂R^1f, —NR^1eSO₂R^1f, oxo, or —CN, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^1g;
  • [0086] R^1e and R^1f are each independently selected from hydrogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^1h;
  • [0087] R^1g and R^1h are each independently selected from hydrogen, halogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, —C_1-8alkyl, —C_1-8alkoxy, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —CN, —OH, —NH₂, and oxo;
  • [0088] R^2a, R^2b, R^2c, R^2d, R^2e, R^2f, R^2g, R^2h, R²ⁱ and R^2j are each independently selected from hydrogen, halogen, —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, and 3- to 8-membered heterocyclyl, wherein each of said —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with at least one substituent R^2aa; or
  • [0089] (R^2b and R^2c), (R^2d and R^2e), (R^2f and R^2g) or (R²ⁱ and R^2j) taking together with the atom to which they are attached, form a 3- to 8-membered unsaturated or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring is optionally substituted with at least one substituent R^2aa;
  • [0090] R^2aa is independently hydrogen, halogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —OR^2ab, —SO₂R^2ab, —SO₂NR^2abR^2ac, —COR^2ab, —CO₂R^2ab, —CONR^2abR^2ac, —NR^2abR^2ac, —NR^2abCOR^2ac, —NR^2abCO₂R^2ac, —NR^2abSO₂R^2ac, oxo, or —CN, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^2ad;
  • [0091] R^2ab and R^2ac are each independently selected from hydrogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^2ae;
  • [0092] R^2ad and R^2ae are each independently hydrogen, halogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —OR^2af, —SO₂R^2af, —SO₂NR^2afR^2ag, —COR^2af, —CO₂R^2af, —CONR^2afR^2ag, —NR^2afR^2ag, —NR^2afCOR^2ag, —NR^2afCO₂R^2ag, —NR^2afSO₂R^2ag, oxo, or —CN, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, —C₃-C₁₂cycloalkenyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^2ah;
  • [0093] R^2af and R^2ag are each independently selected from hydrogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl, and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R^2ai;
  • [0094] R^2ah and R^2ai are each independently hydrogen, halogen, —C_1-8alkyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl, wherein each of said —C_1-8alkyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 12-membered heterocyclyl, —C₆-C₁₂aryl and 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, —C_1-8alkyl, —C_1-8alkoxy, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —CN, —OH, —NH₂ or oxo;
  • [0095] R^2k are each independently selected from hydrogen, halogen, —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, and 3- to 8-membered heterocyclyl, wherein each of said —C_1-8alkyl, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with at least one substituent halogen, —C_1-8alkyl, —C_1-8alkoxy, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, 5- to 12-membered heteroaryl, —CN, —OH, —NH₂ or oxo;
  • [0096] R³ is selected from hydrogen, halogen, —C_1-8alkyl, —C₃-C₈cycloalkyl, —CN, —OH, and —NH₂, wherein each of said —C_1-8alkyl and —C₃-C₈cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of halogen, —C_1-8alkoxy, —C_1-8alkyl, —C₃-C₈cycloalkyl, and 3- to 8-membered heterocyclyl;
  • [0097] R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, halogen, —C_1-8alkyl, and —C₃-C₈cycloalkyl, wherein each of said —C_1-8alkyl and —C₃-C₈cycloalkyl is optionally substituted with at least one substituent selected from the group consisting of halogen, —C_1-8alkoxy, —C_1-8alkyl, —C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, C₆-C₁₂aryl, 5- to 12-membered heteroaryl, oxo, —CN, —OR^4a, —SO₂R^4a, —SO₂NR^4aR^4b, —COR^4a, —CO₂R^4a, —CONR^4aR^4b, —NR^4aR^4b, —NR^4aCOR^4b, —NR^4aCO₂R^4b, and —NR^4aSO₂R^4b;
  • [0098] R^4a and R^4b are each independently hydrogen, —C_1-8alkyl, C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, or 5- to 12-membered heteroaryl; each of said —C_1-8alkyl, C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one halogen, —OH, —C_1-8alkyl, —C_1-8alkoxy, C_1-8alkoxy-C_1-8alkyl-, —C_2-8alkenyl, —C_2-8alkynyl, —C₃-C₈cycloalkyl, 3- to 8-membered heterocyclyl, —C₆-C₁₂aryl, or 5- to 12-membered heteroaryl.
    In one embodiment, the compound is Formula (IIa):

Methods for Making Compounds

General Synthesis

Synthesis of the Acid Building Blocks (Intermediate P)

Synthesis of the Amine Building Blocks (Intermediate Q)

Synthesis of Compounds of Formula (I)

EXAMPLES

Abbreviations

EXAMPLES

Example 1 & Example 2: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: ethyl 4-amino-1H-pyrrole-2-carboxylate

Step 2: ethyl 4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate

Step 3: ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1H-pyrrole-2-carboxylate

Step 4: ethyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate

Step 5: ethyl 4-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate

Step 6: ethyl 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate

Step 7: 5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid

Step 8: 1-benzyl-4-(3-methoxybenzyl)-3,4-dihydropyridin-2(1H)-one

Step 9: 2-benzyl-8-methoxy-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 10: 2-benzyl-8-methoxy-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 11: 2-benzyl-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocin-8-ol

Step 12: 2-benzyl-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocin-8-yl trifluoromethanesulfonate

Step 13: 2-benzyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 14: 2-benzyl-8-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 15: 8-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 16: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 17: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 3 & Example 4: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1,4-dibenzyl-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 2-benzyl-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocine-3(2H)-thione

Step 4: 1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 5: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 6: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 5 & Example 6: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-methyl-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-methyl-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-benzyl-4-(3-methylbenzyl)-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-8-methyl-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 2-benzyl-8-methyl-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocine-3(2H)-thione

Step 4: 8-methyl-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 5: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-methyl-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 6: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-methyl-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-methyl-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 7 & Example 8: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-cyclopropyl-10-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-cyclopropyl-10-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-(bromomethyl)-3-cyclopropyl-5-fluorobenzene

Step 2: 1-benzyl-4-(3-cyclopropyl-5-fluorobenzyl)-3,4-dihydropyridin-2(1H)-one

Step 3: 2-benzyl-8-cyclopropyl-10-fluoro-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 4: 2-benzyl-8-cyclopropyl-10-fluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 5: 8-cyclopropyl-10-fluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 6: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-cyclopropyl-10-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 7: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-cyclopropyl-10-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-cyclopropyl-10-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 9 & Example 10: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-benzyl-4-(3-fluorobenzyl)-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-8-fluoro-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 8-fluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 4: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-fluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 11 & Example 12: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8,10-difluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8,10-difluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-benzyl-4-(3,5-difluorobenzyl)-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-8,10-difluoro-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 8,10-difluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 4: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8,10-difluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8,10-difluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8,10-difluoro-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 13 & 14: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-bromo-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-bromo-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-benzyl-4-(3-bromobenzyl)-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-8-bromo-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 8-bromo-1,4,5,6-tetrahydro-15-methanobenzo[c]azocin-3(2H)-one

Step 4: 8-bromo-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 5: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-bromo-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 6: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-bromo-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-bromo-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 15 & Example 16: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 1: 1-benzyl-4-(3-fluoro-5-methoxybenzyl)-3,4-dihydropyridin-2(1H)-one

Step 2: 2-benzyl-10-fluoro-8-methoxy-1,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-3(2H)-one

Step 3: 2-benzyl-10-fluoro-8-methoxy-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 4: 2-benzyl-10-fluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocin-8-ol

Step 5: 2-benzyl-10-fluoro-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocin-8-yl trifluoromethanesulfonate

Step 6: 2-benzyl-10-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 7: 2-benzyl-10-fluoro-8-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 8: 10-fluoro-8-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,5-methanobenzo[c]azocine

Step 9: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Step 10: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 17 & Example 18: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: ethyl 2-methyl-4-(trifluoromethyl)benzoate

Step 2: ethyl 2-(bromomethyl)-4-(trifluoromethyl)benzoate

Step 3: ethyl 2-((benzyl(2-ethoxy-2-oxoethyl)amino)methyl)-4-(trifluoromethyl)benzoate

Step 4: ethyl 2-benzyl-4-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Step 5: 2-benzyl-7-(trifluoromethyl)-2,3-dihydroisoquinolin-4(1H)-one

Step 6: 4-hydroxy-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-2-ium acetate

Step 7: tert-butyl (2-(4-hydroxy-7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)carbamate

Step 8: 2-(2-aminoethyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol dihydrochloride

Step 9: N-(2-(4-hydroxy-7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-nitrobenzenesulfonamide

Step 10: 8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine

Step 11: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 12: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 19 & Example 20: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: methyl (3-bromo-5-fluorobenzyl)glycinate

Step 2: methyl N-((benzyloxy)carbonyl)-N-(3-bromo-5-fluorobenzyl)glycinate

Step 3: N-((benzyloxy)carbonyl)-N-(3-bromo-5-fluorobenzyl)glycine

Step 4: 7-bromo-5-fluoro-2,3-dihydroisoquinolin-4(1H)-one & 5-bromo-7-fluoro-2,3-dihydroisoquinolin-4(1H)-one

Step 5: 7-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinolin-4-ol & 5-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinolin-4-ol

Step 6: tert-butyl 7-bromo-5-fluoro-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate & tert-butyl 5-bromo-7-fluoro-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 7: tert-butyl 7-bromo-5-fluoro-4-((2-hydroxyethyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate & tert-butyl 5-bromo-7-fluoro-4-((2-hydroxyethyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 9: tert-butyl 8-bromo-10-fluoro-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 9: tert-butyl 10-fluoro-8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 10: tert-butyl 10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 11: 10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 12: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 13: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 21 & Example 22: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: ethyl 2-((benzyl(2-ethoxy-2-oxoethyl)amino)methyl)benzoate

Step 2: ethyl 2-benzyl-4-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Step 3: 2-benzyl-2,3-dihydroisoquinolin-4(1H)-one

Step 4: 4-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-ium acetate

Step 5: tert-butyl (2-(4-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)carbamate

Step 6: 2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-4-ol dihydrochloride

Step 7: N-(2-(4-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2-nitrobenzenesulfonamide

Step 8: 1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine

Step 9: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 10: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 23 & Example 24: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: methyl (3-bromobenzyl)glycinate

Step 2: methyl N-((benzyloxy)carbonyl)-N-(3-bromobenzyl)glycinate

Step 3: N-((benzyloxy)carbonyl)-N-(3-bromobenzyl)glycine

Step 4: tert-butyl 7-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 5: tert-butyl 7-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 6: tert-butyl 7-bromo-4-((2-hydroxyethyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 7: 8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine

Step 8: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 9: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 25: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-cyclopropyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl 8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 2: tert-butyl 8-cyclopropyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 3: 8-cyclopropyl-13,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 4: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-cyclopropyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-cyclopropyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 26 & Example 27: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: 2-methyl-4-oxotetrahydrofuran-3-carbonitrile

Step 2: 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate

Step 3: ethyl 4-((tert-butoxycarbonyl)amino)-5-(4-cyano-5-methyl-2,5-dihydrofuran-3-yl)-1H-pyrrole-2-carboxylate

Step 4: ethyl (S)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate & ethyl (R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylate

Step 5: (R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridine-2-carboxylic acid

Step 6: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 28 & Example 29: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-bromo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 30 & Example 31: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl 8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 2: 8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine

Step 3: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 4: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-iodo-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 32: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-bromo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl (2-(3-bromophenyl)propan-2-yl)glycinate

Step 2: (2-(3-bromophenyl)propan-2-yl)glycine hydrochloride

Step 3: 7-bromo-1,1-dimethyl-2,3-dihydroisoquinolin-4(1H)-one

Step 4: 2-acetyl-7-bromo-1,1-dimethyl-2,3-dihydroisoquinolin-4(1H)-one

Step 5: 1-(7-bromo-4-hydroxy-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

Step 6: 1-(7-bromo-4-((2-hydroxyethyl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

Step 7: 2-((7-bromo-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)ethan-1-ol

Step 8: 8-bromo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine

Step 9: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-bromo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 10: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-bromo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 33 & Example 34: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6S)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6R)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: methyl (1-(3-bromophenyl)ethyl)glycinate

Step 2: methyl N-((benzyloxy)carbonyl)-N-(1-(3-bromophenyl)ethyl)glycinate

Step 3: N-((benzyloxy)carbonyl)-N-(1-(3-bromophenyl)ethyl)glycine

Step 4: tert-butyl 7-bromo-1-methyl-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 5: tert-butyl (4R)-7-bromo-4-hydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 6: tert-butyl (4S)-7-bromo-4-((2-hydroxyethyl)amino)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 7: tert-butyl (1S,5S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 8: tert-butyl (1S,5S)-8-iodo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 9: tert-butyl (1S,5S)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 10: (1S,5S)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine bis(trifluoroacetic acid)

Step 11: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S′)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 12: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6S)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6R)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 35 & Example 36: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6S)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6R)-6-methyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 37 & Example 38: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 1: 7-(trifluoromethyl)-4H-chromen-4-one

Step 2: 2-allyl-7-(trifluoromethyl)chroman-4-one

Step 3: 2-(4-oxo-7-(trifluoromethyl)chroman-2-yl)acetaldehyde

Step 4: 2-(2-hydroxyethyl)-7-(trifluoromethyl)chroman-4-ol

Step 5: 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(trifluoromethyl)chroman-4-ol

Step 6: tert-butyl (2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(trifluoromethyl)chroman-4-yl)((2-nitrophenyl)sulfonyl)carbamate

Step 7: N-(2-(2-hydroxyethyl)-7-(trifluoromethyl)chroman-4-yl)-2-nitrobenzenesulfonamide

Step 8: 5-((2-nitrophenyl)sulfonyl)-9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 9: 9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 10: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 11: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 39 & Example 40: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-bromo-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-bromo-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 1: 2-allyl-7-bromochroman-4-one

Step 2: 2-(7-bromo-4-oxochroman-2-yl)acetaldehyde

Step 3: 7-bromo-2-(2-hydroxyethyl)chroman-4-ol

Step 4: 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)chroman-4-ol

Step 5: tert-butyl (7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)chroman-4-yl)((2-nitrophenyl)sulfonyl)carbamate

Step 6: N-(7-bromo-2-(2-hydroxyethyl)chroman-4-yl)-2-nitrobenzenesulfonamide

Step 7: 9-bromo-5-((2-nitrophenyl)sulfonyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 8: 9-bromo-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 9: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(9-bromo-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 10: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-bromo-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-bromo-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 41 & Example 42: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 1: 1-(4-bromo-2-fluoro-6-hydroxyphenyl)ethan-1-one

Step 2: 7-bromo-5-fluoro-4H-chromen-4-one

Step 3: 5-fluoro-7-(trifluoromethyl)-4H-chromen-4-one

Step 4: 2-allyl-5-fluoro-7-(trifluoromethyl)chroman-4-one

Step 5: 2-(5-fluoro-4-oxo-7-(trifluoromethyl)chroman-2-yl)acetaldehyde

Step 6: 5-fluoro-2-(2-hydroxyethyl)-7-(trifluoromethyl)chroman-4-ol

Step 7: 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-7-(trifluoromethyl)chroman-4-ol

Step 8: tert-butyl (2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-7-(trifluoromethyl)chroman-4-yl)((2-nitrophenyl)sulfonyl)carbamate

Step 9: N-(5-fluoro-2-(2-hydroxyethyl)-7-(trifluoromethyl)chroman-4-yl)-2-nitrobenzenesulfonamide

Step 10: 7-fluoro-5-((2-nitrophenyl)sulfonyl)-9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 11: 7-fluoro-9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 12: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 13: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 43 & Example 44: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 45 & Example 46: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 47 & Example 48: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-10-fluoro-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 49 & Example 50: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5R)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5S)-8-(trifluoromethyl)-3,4,5,6-tetrahydro-1,5-methanobenzo[c]azocin-2(1H)-yl)methanone

Example 51: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-ethynyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 2: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-ethynyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 52 & Example 53: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl 8-bromo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 2: tert-butyl 8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 3: 8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 4: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 54 & Example 55: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-8-iodo-6,6-dimethyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 56 & Example 57: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl 6,6-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 2: tert-butyl 6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 3: 6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 4: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 58 & Example 59: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-6,6-dimethyl-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 60 & Example 61: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-5(2H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-5(2H)-yl)methanone

Step 1: 6-(2-nitro-4-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one

Step 2: 9-(trifluoromethyl)-2,3,5,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-4(1H)-one

Step 3: tert-butyl 9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocine-5(2H)-carboxylate

Step 4: tert-butyl 1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocine-5(2H)-carboxylate

Step 5: 1-methyl-9-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[b][1,5]diazocine hydrochloride

Step 6: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-5(2H)-yl)methanone

Step 7: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-5(2H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-1-methyl-9-(trifluoromethyl)-1,3,4,6-tetrahydro-2,6-methanobenzo[b][1,5]diazocin-5(2H)-yl)methanone

Example 62 & Example 63: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1'S,5'S)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Step 1: ethyl (1-(3-bromophenyl)cyclopropyl)glycinate

Step 2: ethyl N-((benzyloxy)carbonyl)-N-(1-(3-bromophenyl)cyclopropyl)glycinate

Step 3: N-((benzyloxy)carbonyl)-N-(1-(3-bromophenyl)cyclopropyl)glycine

Step 4: 7′-bromo-2′,3′-dihydro-4′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-one

Step 5: 1-(7′-bromo-4′-hydroxy-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-2′-yl)ethan-1-one

Step 6: 1-(7′-bromo-4′-((2-hydroxyethyl)amino)-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-2′-yl)ethan-1-one

Step 7: 2-((7′-bromo-3′,4′-dihydro-2′H-spiro[cyclopropane-1,1′-isoquinolin]-4′-yl)amino)ethan-1-ol

Step 8: tert-butyl 8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocine]-2′(1′H)-carboxylate

Step 9: tert-butyl 8′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocine]-2′(1′H)-carboxylate

Step 10: tert-butyl 8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocine]-2′(1′H)-carboxylate

Step 11: 8′-(trifluoromethyl)-1′,2′,3′,4′-tetrahydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocine]dihydrochloride

Step 12: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Step 13: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1'S,5'S)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Example 64 & Example 65: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocin-5(6H)-yl)methanone

Step 1: 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)piperidin-4-one

Step 2: tert-butyl 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-4-oxopiperidine-1-carboxylate

Step 3: tert-butyl 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

Step 4: tert-butyl 9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocine-5(6H)-carboxylate

Step 5: 9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocine

Step 6: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocin-5(6H)-yl)methanone

Step 7: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanopyrido[2,3-b][1,5]oxazocin-5(6H)-yl)methanone

Example 66 & Example 67: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: tert-butyl 7-bromo-4-hydroxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 2: tert-butyl 7-bromo-4-((2-hydroxyethyl)amino)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

Step 2: rac-tert-butyl (1R,5R,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate & rac-tert-butyl (1R,5R,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine-2-carboxylate

Step 3: rac-(1R,5R,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 4: rac-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 5: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 68 & Example 69: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 1: rac-(1R,5R,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocine dihydrochloride

Step 2: rac-(5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Step 3: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1R,5R,6S)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S,6R)-8-bromo-6-methyl-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Example 70 & Example 71: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 1: 2-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)piperidin-4-one

Step 2: tert-butyl 2-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)-4-oxopiperidine-1-carboxylate

Step 3: tert-butyl 2-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)-4-hydroxy-4-methylpiperidine-1-carboxylate

Step 4: tert-butyl 7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocine-5(6H)-carboxylate

Step 5: 7-fluoro-2-methyl-9-(trifluoromethyl)-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[b][1,5]oxazocine

Step 6: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Step 7: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 72 & Example 73: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2S,6R)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((2R,6S)-7-fluoro-2-methyl-9-(trifluoromethyl)-3,4-dihydro-2H-2,6-methanobenzo[b][1,5]oxazocin-5(6H)-yl)methanone

Example 74 & Example 75: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′S,5′S)-8′-bromo-3′,4′-dihydro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Step 1: 8′-bromo-1′,2′,3′,4′-tetrahydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocine]dihydrochloride

Step 2: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1'S,5'S)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Example 76 & Example 77: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′S,5′S)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Step 1: (5-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)(8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Step 2: (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & (5-amino-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′S,5′S)-8′-bromo-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Example 78 & Example 79: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′R,5′R)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone & ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1′S,5 S)-8′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclopropane-1,6′-[1,5]methanobenzo[f][1,4]diazocin]-2′(1′H)-yl)methanone

Example 80: ((R)-5-amino-6-methyl-6,8-dihydro-1H-furo[3,4-d]pyrrolo[3,2-b]pyridin-2-yl)((1S,5S)-10-fluoro-8-(trifluoromethyl)-1,3,4,6-tetrahydro-2H-1,5-methanobenzo[f][1,4]diazocin-2-yl)methanone

Assays

Cell Killing in HCT116 Isogenic Pair

Experimental