RU2824583C2 - Substituted pyrrolo[2,3-b]pyridine and pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to compounds which can inhibit Bruton’s tyrosine kinase (BTK) activity, specifically to a compound of formula (II) or a pharmaceutically acceptable salt thereof. In formula (II): ring Q is selected from , and , which are each unsubstituted or substituted with at least one substitute independently selected from R^X; L represents O; X¹, X², X³ and X⁴ independently selected from CR^X’ and N, where not more than 1 of X¹, X², X³ and X⁴ can represent N; R¹ is C_1-10alkyl, where alkyl is unsubstituted or substituted with at least one substituent independently selected from R^X1; R² is selected from hydrogen, halogen, CN, -OR^A2, -C(O)NR^A2R^B2 and C_1-10alkyl, where alkyl is unsubstituted or substituted with at least one substituent independently selected from R^X2; R³ is hydrogen; R⁴ is hydrogen; R⁵ is selected from phenyl and heteroaryl, where phenyl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R^X5; each R^A2 is independently selected from hydrogen, C_1-10alkyl and C_3-10cycloalkyl, where alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R^X2; every R^B2 is hydrogen; each R^X' is independently selected from hydrogen, deuterium, C_1-10alkyl, C_3-10cycloalkyl, halogen, CN and -(CR^c1R^d1)_tOR^b1; each R^X is independently selected from hydrogen, C_1-10alkyl, -(CR^c1R^d1)_tOR^b1, (CR^c1R^d1)_tNR^a1C(O)R^bl, -(CR^clR^dl)tNR^a1C(O)OR^bl and -(CR^clR^d1)_tNR^alS(O)₂NR^alR^bl, where alkyl is unsubstituted or substituted with at least one substituent independently selected from R^Y; each R^X1 is independently selected from hydrogen, halogen, CN, -(CR^clR^dl)tOR^bl, -(CR^clR^dl)_tNR^a1C(O)R^bl, -(CR^clR^dl)_tNR^alC(O)OR^bl, -(CR^clR^dl)_tNR^alC(O)NR^alR^bl, -(CR^clR^dl)_tN=S(O)R^alR^bl, -(CR^clR^dl)_tNR^alS(O)_rR^bl and -(CR^clR^dl)_tNR^alS(O)₂NR^alR^bl; R^X2 is deuterium; each R^X5 is independently selected from hydrogen, halogen, CN, NO₂ and -(CR^clR^dl)_tOR^b1; each R^al and each R^bl is independently selected from hydrogen, C_1-10alkyl and C_3-10cycloalkyl; each R^cl and each R^dl is hydrogen; each R^Y is independently selected from -OR^a2, -(CR^c2R^d2)_tOR^b2, -(CR^c2R^d2)_tNR^a2C(O)R^b2, -(CR^c2R^d2)_tNR^a2CO₂R^b2, -(CR^c2R^d2)_tNR^a2SO₂NR^a2R^b2, -NR^a2C(O)R^b2, -NR^a2C(O)^ORb2, -CHF₂, -CF₃, -OCHF₂ and -OCF₃; each R^a2 and each R^b2 is independently selected from hydrogen and C_1-10alkyl; each R^c2 and each R^d2 is hydrogen; each r is selected from 0, 1 and 2; each t is selected from 0, 1, 2, 3 and 4; heteroaryl is 5–8-membered monocyclic aromatic ring containing one heteroatom selected from N. Also disclosed is a pharmaceutical composition and use of said compound.

EFFECT: disclosed compounds are capable of inhibiting BTK and can be used for treating, relieving or preventing a condition which is caused by BTK inhibition, and for treating cell proliferation disorders.

19 cl, 4 tbl, 198 ex

Description

[1] This application claims priority over U.S. Provisional Application Nos. 62/854,983, 62/904,611, and 62/935,091, each of which is incorporated herein by reference in its entirety.

Field of technology to which the present invention relates

[2] Provided are certain compounds or pharmaceutically acceptable salts thereof that can inhibit the kinase activity of Bruton tyrosine kinase (BTK) and may be useful for the treatment of hyperproliferative diseases such as cancer and inflammation, or immune and autoimmune diseases.

Prior art of the present invention

[3] Hyperproliferative diseases such as cancer and inflammation have attracted the scientific community to provide therapeutic benefits. In this regard, efforts have been made to define and elucidate the specific mechanisms that play a role in the progression of proliferative diseases.

[4] Bruton tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases expressed in B cells and myeloid cells and plays a critical role in B cell receptor (BCR) signaling pathways that are involved in early B cell development as well as mature B cell activation, signaling, and survival.

[5] Functional mutations in human BTK are known to result in X-linked agammaglobulinemia (XLA), an immunodeficiency disorder associated with the failure to form mature B cells, resulting in decreased serum immunoglobulin levels. Furthermore, BTK regulation can influence BCR-induced production of proinflammatory cytokines and chemokines by B cells, indicating a broad potential for BTK in the treatment of autoimmune diseases. Evidence for a role for BTK in autoimmune and inflammatory diseases has also been obtained in BTK-deficient mouse models. Thus, inhibition of BTK activity may be useful for the treatment of autoimmune and/or inflammatory diseases such as rheumatoid arthritis, multiple vasculitides, myasthenia gravis, and asthma.

[6] In addition, BTK has been reported to play an important role in apoptosis. In certain malignancies, BTK is overexpressed in B cells, and this is associated with increased proliferation and survival of tumor cells. Inhibition of BTK affects B cell signaling pathways, preventing B cell activation and inhibiting the growth of malignant B cells.

[7] Thus, inhibition of BTK activity may be useful for the treatment of cancer, as well as for the treatment of B-cell lymphoma, leukemia, and other hematological malignancies. A number of clinical studies have demonstrated that BTK inhibitors are effective against various types of cancer. The first-in-class BTK inhibitor ibrutinib (PCI-32765) has been approved by the US Food and Drug Administration for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and Waldenstrom's macroglobulinemia (WM). BTK inhibitor may also be used to treat other conditions such as immunological diseases and inflammation.

[8] Therefore, a compound having inhibitory activity against BTK, including mutant BTK, will be useful for preventing or treating the previously described diseases. Although BTK inhibitors have been disclosed in the art, such as WO2008039218 and WO2008121742, many have disadvantages such as short half-life or toxicity. Therefore, there is a need for new BTK inhibitors that have at least one advantageous property selected from efficacy, stability, selectivity, toxicity and pharmacodynamic properties, as an alternative for treating hyperproliferative diseases. In this regard, a new class of BTK inhibitors is provided herein.

Disclosure of the present invention

[9] The present invention discloses certain new compounds, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions, and their use as medicinal products.

[10] According to one aspect, the present invention discloses a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

ring Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L is selected from the connection, -(CR ^C0 R ^D0 ) _u -, -(CR ^C0 R ^D0 ) _u O(CR _C0 R _D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR _C0 R _D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C (O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O)r(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O ) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -;

X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N;

Y is selected from CR ⁴ and N;

R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -c( =nr ^e1 )r ^a1 , -C(=N-OR ^B1 )R ^A1 , -C(O)OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C( O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -nr ^a1 c(=nr ^e1 )nr ^a1 r ^b1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S (O)R ^A1 R ^B1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR _A1 S(O)(=NR ^E1 )R ^B1 , -s(o) _r nr ^a1 r ^b1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1 ;

R ² is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X2 ;

R ³ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X3 ;

R ⁴ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A4 R ^B4 , -OR ^A4 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X4 ;

R ⁵ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O)R ^A5 , -C( =NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C( O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S (O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 ;

each R ^A0 and R ^B0 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X0 ;

or each "R ^A0 and R ^B0 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X0 groups;

each R ^A1 and R ^B1 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1 ;

or each "R ^A1 and R ^B1 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X1 groups;

each R ^A2 and R ^B2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X2 ;

or each "R ^A2 and R ^B2 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X2 groups;

each R ^A3 and R ^B3 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X3 ;

or each "R ^A3 and R ^B3 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X3 groups;

each R ^A4 and R ^B4 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X4 ;

or each "R ^A4 and R ^B4 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X4 groups;

each R ^A5 and R ^B5 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 ;

or each "R ^A5 and R ^B5 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X5 groups;

each R ^C0 and R ^D0 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X0 ;

or R ^C0 and R ^D0 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^X0 groups;

each R ^E0 , R ^E1 and R ^E5 is independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ;

R ^X , R ^X' , R ^X0 , R ^X1 , R ^X2 , R ^X3 , R ^X4 and R ^X5 are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C (=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S (O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

each R ^a1 and each R ^b1 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^e1 is independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ;

each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O)rR ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CRc2R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O )R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, - C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r Rb ² , -CR ^a2 (=N-OR ^b2 ), -C(=NR ^e2 )R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C( =NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _{1- 10} alkyl)amino;

each R ^a2 and each R ^b2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _1-10 cycloalkylamino and di(C _1-10 alkyl)amino;

or R ^a2 and R ^b2 , together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^c2 and R ^d2 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ;

each R is independently chosen from 0, 1, and 2;

each t is independently chosen from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3, and 4.

[11] According to one embodiment of formula (I), the present invention relates to a compound or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ , the compound being characterized by formula (II)

where Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are defined in formula (I).

[12] According to another aspect, the present disclosure relates to pharmaceutical compositions comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[13] According to another aspect, the present disclosure relates to methods of modulating BTK, the methods comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof, thereby modulating said BTK.

[14] According to yet another aspect, the present disclosure provides a method of treating, alleviating or preventing a condition that responds to inhibition of BTK, the method comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof, and optionally in combination with a second therapeutic agent for treating said condition.

[15] Alternatively, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a BTK-mediated condition. According to certain embodiments, the compounds of the present disclosure may be used alone or in combination with a second therapeutic agent for the treatment of a BTK-mediated condition.

[16] Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed for the treatment of a BTK-mediated condition.

[17] In particular, the condition described herein includes, but is not limited to, an autoimmune disease, a heteroimmune disease, an allergic disease, an inflammatory disease, or a cell proliferative disorder.

[18] Furthermore, the present disclosure relates to methods of treating a condition mediated by VTC, the method comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

[19] Alternatively, the present disclosure provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a BTK-mediated condition. In specific examples, the compounds of the present disclosure may be used alone or in combination with a chemotherapeutic agent to treat said condition.

[20] In particular, a condition as used herein includes, but is not limited to, an autoimmune disease, a heteroimmune disease, an allergic disease, an inflammatory disease, or a cell proliferative disorder.

[21] According to certain embodiments, the condition is a cell proliferative disorder. According to one embodiment, the cell proliferative disorder is a B-cell proliferative disorder, which includes, but is not limited to, B-cell malignancies, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic lymphoma, lymphoplasmacytic lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin lymphoma, activated diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, lymphomatoid granulomatosis, and plasmacytoma.

[22] According to certain embodiments, the condition is an autoimmune disease, which includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, myasthenia gravis, Hashimoto's thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, dysautonomia, neuromyotonia, interstitial cystitis, lupus, systemic lupus erythematosus, and lupus nephritis.

[23] According to certain embodiments, the condition is a heteroimmune disease, which includes, but is not limited to, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[24] According to certain embodiments, the condition is an inflammatory disease that includes, but is not limited to, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, endonitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

[25] In the above-mentioned methods of using the compounds of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system containing cells or tissues or to a subject, including a mammalian subject, such as a human subject or an animal subject.

Defined Terminology

[26] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in the art to which the claimed subject matter belongs. All patents, patent applications, and published works referenced throughout this disclosure, unless otherwise noted, are incorporated by reference in their entirety. In the event of multiple definitions of terms in this document, the definition in this section shall govern.

[27] It should be understood that the foregoing general description and the following detailed description are merely illustrative and explanatory and are not limiting of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically indicated otherwise. It should be noted that the singular as used herein and in the appended claims includes the plural of the identified items unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless otherwise indicated. In addition, the use of the term "including", as well as other forms such as "include", "includes" and "included", is not limiting. Likewise, the use of the term "comprising", as well as other forms such as "contain", "comprises" and "contained" is not limiting.

[28] Unless otherwise indicated, conventional techniques of mass spectroscopy, NMR, HPLC, IR, and ultraviolet-visible spectroscopy and pharmacology used by those skilled in the art are used. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry used in this regard disclosed herein are those recognized in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. Reactions and purification techniques may be performed, for example, using manufacturer's specification sets, or as routinely performed in the art, or as disclosed herein. The aforementioned techniques and procedures may generally be performed by conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. Throughout the description, groups and their substituents can be selected by a person skilled in the art to provide stable fragments and compounds.

[29] While substituent groups are characterized by their traditional chemical formulas written from left to right, they equally encompass chemically identical substituents that arise from writing the structure from right to left. As a non-limiting example, CH ₂ O is equivalent to OCH ₂ .

[30] The term "substituted" means that the hydrogen atom is replaced by a substituent. It will be understood that the substitution at a given atom is limited by valence.

[31] As used herein, the term "C _ij " or "ij membered" means that the moiety contains ij carbon atoms or ij atoms. For example, "C _1-6 alkyl" means that the specified alkyl contains 1-6 carbon atoms. Similarly, C _3-10 cycloalkyl means that the specified cycloalkyl contains 3-10 carbon atoms.

[32] If any variable (e.g., R) occurs more than once in the structure of a compound, it is independently defined in each occurrence. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, and R is characterized by an independent variant in each occurrence. Furthermore, a combination of substituents and/or their variants is permitted only if such a combination will result in a stable compound.

[33] The expression "one or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

[34] Unless otherwise stated, the term "hetero" means a heteroatom or a heteroatomic radical (i.e., a radical containing a heteroatom), i.e., atoms other than carbon and hydrogen atoms or a radical containing such atoms. Preferably, the heteroatom(s) are independently selected from the group consisting of O, N, S, P, etc. According to an embodiment, if two or more heteroatoms are included, the two or more heteroatoms may be the same, or some or all of the two or more heteroatoms may be different.

[35] The term "alkyl," used alone or in combination with other terms, refers to saturated aliphatic hydrocarbon groups, both straight-chain and branched, containing the specified number of carbon atoms. Unless otherwise noted, "alkyl" refers to C _1-10 alkyl. For example, C _1-6 , as in "C _1-6 alkyl" is defined to include groups containing 1, 2, 3, 4, 5, or 6 carbon atoms in a straight-chain or branched arrangement. For example, "C _1-8 alkyl" includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

[36] The term "cycloalkyl", used alone or in combination with other terms, refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically with from 3 to 16 ring atoms. The ring atoms of a cycloalkyl are all carbon atoms and a cycloalkyl contains zero heteroatoms and zero double bonds. In a polycyclic cycloalkyl, two or more rings may be fused or bridged or spiro together. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms that contains one or two alkylene bridges, each alkylene bridge consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. The cycloalkyl may be fused to an aryl or heteroaryl group. According to some embodiments, the cycloalkyl is benzofused. Illustrative examples of such bridged cycloalkyl ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03.7]nonane, and tricyclo[3.3.1.13.7]decane (adamantane). The monocyclic cycloalkyl or bridged cycloalkyl may be attached to the parent molecular moiety through any replaceable atom contained in the ring system.

[37] The term "alkenyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon radical, straight, branched, or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond. According to some embodiments, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C _2-6 alkenyl" means an alkenyl radical containing from 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight, branched, or cyclic portion of an alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is specified.

[38] The term "alkynyl," used alone or in combination with other terms, refers to a hydrocarbon radical, straight, branched, or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. According to some embodiments, up to three carbon-carbon triple bonds may be present. Thus, "C _2-6 alkynyl" means an alkynyl radical containing from 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and 3-methylbutynyl. The straight, branched, or cyclic portion of an alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is specified.

[39] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, or iodine.

[40] The term "alkoxy", used alone or in combination with other terms, refers to an alkyl, as defined above, which is attached by a single bond to an oxygen atom. The point of attachment of the alkoxy radical to the molecule is through the oxygen atom. The alkoxy radical may be depicted as -O-alkyl. The term "C _1-10 alkoxy" refers to an alkoxy radical containing 1-10 carbon atoms, containing straight or branched moieties. An alkoxy group includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

[41] The term "cycloalkoxy" used alone or in combination with other terms refers to a cycloalkyl, as defined above, that is bonded by a single bond to an oxygen atom. The point of attachment of the cycloalkoxy radical to the molecule is through the oxygen atom. The cycloalkoxy radical may be depicted as -O-cycloalkyl. "C _3-10 cycloalkoxy" refers to a cycloalkoxy radical containing 3-10 carbon atoms. Cycloalkoxy may be fused with an aryl or heteroaryl group. According to some embodiments, the cycloalkoxy is benzo-fused. The cycloalkoxy group includes, but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

[42] The term "alkylthio", used alone or in combination with other terms, refers to an alkyl radical, as defined above, which is attached by a single bond to a sulfur atom. The point of attachment of the alkylthio radical to the molecule is through the sulfur atom. An alkylthio radical may be depicted as -S-alkyl. The term "C _1-10 alkylthio" refers to an alkylthio radical containing 1-10 carbon atoms, containing straight or branched moieties. An alkylthio group includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

[43] The term "cycloalkylthio," used alone or in combination with other terms, refers to a cycloalkyl, as defined above, that is bonded by a single bond to a sulfur atom. The point of attachment of the cycloalkylthio radical to the molecule is through the sulfur atom. The cycloalkylthio radical may be depicted as -S-cycloalkyl. "C _3-10 cycloalkylthio" refers to a cycloalkylthio radical containing 3-10 carbon atoms. The cycloalkylthio may be fused to an aryl or heteroaryl group. According to some embodiments, the cycloalkylthio is benzofused. The cycloalkylthio group includes, but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

[44] The term "alkylamino", used alone or in combination with other terms, refers to an alkyl, as defined above, which is bonded by a single bond to a nitrogen atom. The point of attachment of the alkylamino radical to the molecule is through the nitrogen atom. The alkylamino radical may be depicted as -NH(alkyl). The term "C _1-10 alkylamino" refers to an alkylamino radical containing 1-10 carbon atoms, containing straight or branched moieties. An alkylamino group includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, and the like.

[45] The term "cycloalkylamino," used alone or in combination with other terms, refers to a cycloalkyl, as defined above, that is bonded by a single bond to a nitrogen atom. The point of attachment of the cycloalkylamino radical to the molecule is through the nitrogen atom. The cycloalkylamino radical may be depicted as -NH(cycloalkyl). "C _3-10 cycloalkylamino" refers to a cycloalkylamino radical containing 3-10 carbon atoms. The cycloalkylamino may be fused to an aryl or heteroaryl group. According to some embodiments, the cycloalkylamino is benzo-fused. The cycloalkylamino group includes, but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.

[46] The term "di(alkyl)amino", used alone or in combination with other terms, refers to two alkyls, as defined above, which are linked by a single bond to a nitrogen atom. The point of attachment of the di(alkyl)amino radical to the molecule is through the nitrogen atom. The di(alkyl)amino radical may be depicted as -N(alkyl) ₂ . The term "di(C _1-10 alkyl)amino" refers to a di(C _1-10 alkyl)amino radical, each of the alkyl radicals independently containing 1-10 carbon atoms, containing straight or branched moieties.

[47] The term "aryl", used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a "C _6-14 aryl" group), in particular a ring containing 6 carbon atoms (a "C ₆ aryl" group), for example a phenyl group; or a ring containing 10 carbon atoms (a "C ₁₀ aryl" group), for example a naphthyl group; or a ring containing 14 carbon atoms (a "C ₁₄ aryl" group), for example an anthranyl group. The aryl may be fused to a cycloalkyl or heterocyclic group.

[48] Divalent radicals formed from substituted benzene derivatives and characterized by free valences at the ring atoms are named as substituted phenylene radicals. Divalent radicals obtained from monovalent polycyclic hydrocarbon radicals whose name ends in "-yl" by removing one hydrogen atom from the carbon atom with the free valence are named by removing the "-yl" and adding "-idene" to the name of the corresponding monovalent radical, e.g., a naphthyl group with two attachment points is named naphthylidene.

[49] The term “heteroaryl”, used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), in particular 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom, which may be identical or different, said heteroatom being selected from N, O and S, with the remaining atoms being carbon. Heteroaryl may be fused to a cycloalkyl or heterocyclyl group. According to some embodiments, “heteroaryl” refers to

a 5-8 membered monocyclic aromatic ring containing one or more, such as 1 to 4, or in some embodiments 1 to 3, heteroatoms selected from N, O and S, with the remaining atoms being carbon; or

an 8- to 12-membered bicyclic aromatic ring system comprising one or more, such as 1 to 6, or in some embodiments 1 to 4, or in some embodiments 1 to 3, heteroatoms selected from N, O and S, with the remaining atoms being carbon; or

An 11- to 14-membered tricyclic aromatic ring system comprising one or more, for example 1 to 8, or in some embodiments 1 to 6, or in some embodiments 1 to 4, or in some embodiments 1 to 3, heteroatoms selected from N, O and S, with the remaining atoms being carbon.

[50] If the total number of S and O atoms in a heteroaryl group exceeds 1, its heteroatoms are not adjacent to each other. According to some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 2. According to some embodiments, the total number of S and O atoms in an aromatic heterocycle is no more than 1.

[51] Examples of heteroaryl groups include, but are not limited to, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.

[52] Additional heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuryl, benzoimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl. It is also understood that "heteroaryl" includes the N-oxide derivative of any nitrogen-containing heteroaryl.

[53] Divalent radicals derived from monovalent heteroaryl radicals whose names end in "-yl" by removing one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding monovalent radical, e.g. a pyridyl group with two points of attachment is pyridylidene.

[54] The term "heterocycle", used alone or in combination with other terms (and variations thereof such as "heterocyclic" or "heterocyclyl"), broadly refers to a saturated or unsaturated mono- or polycyclic (e.g., bicyclic) aliphatic ring system, typically with 3 to 12 ring atoms, wherein at least one (e.g., 2, 3, or 4) ring atoms is a heteroatom independently selected from O, S, N, and P (preferably O, S, N), with the remaining ring atoms being carbon. In a polycyclic heterocycle, two or more rings may be fused or linked together by bridge bonds or spiro bonds. The heterocycle may be fused to an aryl or heteroaryl group. According to some embodiments, the heterocycle is benzofused. The heterocycle also includes ring systems substituted with one or more oxo or imino moieties. According to some embodiments, the C, N, S, and P atoms in the heterocyclic ring are optionally substituted with oxo. According to some embodiments, the C, S, and P atoms in the heterocyclic ring are optionally substituted with imino, and the imino may be unsubstituted or substituted. The point of attachment may be a carbon atom or a heteroatom in the heterocyclic ring, so long as the attachment results in the formation of a stable structure. If the heterocyclic ring contains substituents, it is understood that the substituents may be attached to any atom in the ring, or a heteroatom, or a carbon atom, so long as it results in a stable chemical structure.

[55] Suitable heterocycles include, for example, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-3-yl, imidazolidin-4-yl, imidazolidin-5-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, hexahydropyridazin-1-yl, hexahydropyridazin-3-yl and hexahydropyridazin-4-yl. Morpholinyl groups have also been considered, such as morpholin-1-yl, morpholin-2-yl, and morpholin-3-yl. Examples of a heterocycle with one or more oxo moieties include, but are not limited to, piperidinyl N-oxide, morpholinyl N-oxide, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Bicyclic heterocycles include, for example:

[56] As used herein, "arylalkyl" refers to an alkyl moiety substituted with an aryl group as defined above. Exemplary arylalkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl groups. According to some embodiments, arylalkyl groups contain 7-20 or 7-11 carbon atoms. When using the phrase "aryl-C _1-4 alkyl," the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.

[57] As used herein, "heterocyclylalkyl" refers to alkyl substituted with heterocyclyl, as defined above. When using the expression "heterocyclyl-C _1-4 alkyl," the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.

[58] As used herein, "cycloalkylalkyl" refers to alkyl substituted with cycloalkyl as defined above. When using the expression " _C3-10 cycloalkyl- _C1-4 alkyl", the term " _C3-10 " refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety, and the term " _C1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.

[59] As used herein, "heteroarylalkyl" refers to alkyl, as defined above, substituted with heteroaryl, as defined above. When using the expression "heteroaryl-C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.

[60] For the avoidance of doubt, reference to, for example, substitution of alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl refers to substitution of each of these groups individually, as well as to substitutions of combinations of such groups. Thus, where R is aryl-C _1-4 alkyl and may be unsubstituted or substituted by at least one substituent, for example, one, two, three or four substituents, independently selected from R ^X , it is to be understood that the aryl moiety may be unsubstituted or substituted by at least one substituent, for example, one, two, three or four substituents, independently selected from R ^X , and the alkyl moiety may also be unsubstituted or substituted by at least one substituent, for example, one, two, three or four substituents, independently selected from R ^X .

[61] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts prepared from inorganic bases can be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, ferric, manganese, potassium, sodium and zinc salts. Further, for example, pharmaceutically acceptable salts prepared from inorganic bases can be selected from ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form can exist in one or more crystalline forms or polymorphs, and can also be in the form of solvates such as hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases can be selected, for example, from salts of primary, secondary and tertiary amines, substituted amines including substituted amines of natural origin, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

[62] If the compound disclosed in the present invention is basic, salts can be prepared using at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. Such an acid can be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethic, lactic, maleic, malic, mandelic, methanesulfonic, mucinous, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric and p-toluenesulfonic acids. According to some embodiments, such an acid can be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

[63] It should be understood that the terms “administering” and/or “carrying out the administration” of a compound or a pharmaceutically acceptable salt thereof mean providing a subject with the compound or a pharmaceutically acceptable salt thereof in a recognized need for treatment.

[64] The term "effective amount" means the amount of a compound or pharmaceutically acceptable salt that will elicit the biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[65] As used herein, the term "composition" is intended to cover a product containing specified ingredients in specified amounts, as well as any product that results, directly or indirectly, from the combination of specified ingredients in specified amounts. It is intended that such term, when used with respect to a pharmaceutical composition, covers a product containing active ingredient(s) and inert ingredient(s) that constitute a carrier, as well as any product that results, directly or indirectly, from the combination, complexation, or aggregation of any two or more ingredients, or from the disintegration of one or more ingredients, or from other types of reactions or interactions of one or more ingredients.

[66] The term "pharmaceutically acceptable" means compatible with other ingredients of the formulation and not unacceptably harmful to the recipient.

[67] As used herein, the term "subject" in relation to objects suffering from a disorder, condition, etc., includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other catarrhine monkeys, and other monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, guinea pigs, etc. Examples of non-mammals include birds, fish, etc. According to one embodiment of the methods and compositions provided herein, the mammal is a human.

[68] The terms "treat," "treatment," or "treatment" and other grammatical equivalents as used herein include alleviating, ameliorating, or alleviating a disease or condition, preventing additional symptoms, alleviating or preventing underlying metabolic causes of the symptoms, inhibiting a disease or condition such as stopping the progression of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, reducing a condition caused by a disease or condition, or eliminating symptoms of a disease or condition, and shall also include prophylaxis. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit is defined as eliminating or alleviating the underlying disorder being treated. A therapeutic benefit is also achieved by eliminating or alleviating one or more of the physiological symptoms associated with the underlying disorder such that the patient experiences an improvement although the patient may still suffer from the underlying disorder. For prophylactic use, the compositions may be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of that disease has not been made.

[69] The term "protecting group" or "Pg" refers to a substituent that can typically be used to block or protect certain functional groups when reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amine functionality on a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a substituent on a carboxy group that blocks or protects the carboxy functionality. Traditional _carboxylic acid protecting groups include _-CH2CH2SO2Ph , cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, _2- (p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, etc. For a general description of protecting groups and their uses, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[70] The term "NH-protecting group" as used in the present invention includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-hydroxycyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

[71] The term "C(O)OH protecting group" as used herein includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylylyl.

[72] The term "OH or SH protecting group" as used in the present invention includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-tri chloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2 -methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[73] Geometric isomers may exist in the compounds of the present invention. The compounds of the present invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond, as determined by the Cahn-Ingold-Prelog priority rules. The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocycloalkyl are designated as the cis or trans configuration. Moreover, the present invention contemplates various isomers and mixtures thereof resulting from the arrangement of substituents around the adamantane ring system. Two substituents around a single ring within the adamantane ring system are designated as the Z or E relative configuration. For example, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758–2760.

[74] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry. Pure Appl. Chem. (1976) 45, 13-10. Compounds containing asymmetrically substituted carbon atoms with equal amounts of the R and S configurations are racemic at such carbon atoms. Atoms with an excess of one configuration over the other represent the configuration present in higher amount, preferably in excess of about 85-90%, more preferably in excess of about 95-99%, and still more preferably in excess of more than about 99%. Accordingly, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope enriched or labeled compounds

[75] The compounds of the present invention may exist in isotopically labeled or isotopically enriched form containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Compounds that contain other isotopes of such and/or other atoms are within the scope of the present invention.

[76] According to another embodiment, the isotopically labeled compounds comprise deuterium ( ^2H ), tritium ( ^3H ), or ^14C isotopes. The isotopically labeled compounds of the present invention can be prepared by conventional methods well known to those of ordinary skill in the art. Such isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the examples and schemes described herein by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent. In some cases, the compounds can be treated with isotopically labeled reagents to exchange a normal atom for its isotope, for example, hydrogen can be exchanged for deuterium by the action of a deuterated acid such as _D2SO4 / _{D2O .}

[77] The isotope-labeled compounds of the present invention can be used as standards to determine the potency of BTK inhibitors in binding assays. Isotope-labeled compounds have been used in pharmaceutical research to establish the in vivo metabolic pathway of compounds by assessing the mechanism of action and metabolic pathway of the non-isotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important for the safety and efficacy of therapeutic drugs, either because the in vivo active compound administered to the patient or because metabolites derived from the parent compound have been shown to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Compounds. Radiopharmaceuticals, 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999).

[78] Additionally, non-radioactive isotope-containing drugs, such as deuterated drugs, called "heavy drugs," can be used to treat diseases and conditions associated with BTK activity. Increasing the amount of an isotope present in a compound above its natural occurrence is called enrichment. Examples of enrichment amounts include values from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.

[79] A stable isotopic label of a drug can alter its physicochemical properties such as pKa and lipid solubility. Such effects and changes can impact the pharmacodynamics and response of the drug molecule if the isotopic substitution affects a site involved in ligand-receptor interactions. Although some of the physical properties of a stable isotopically labeled molecule differ from that of the unlabeled molecule, the chemical and biological properties are the same with one important exception: due to the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between a lighter isotope and that atom. Accordingly, incorporation of an isotope into a metabolic site or enzymatic conversion will slow down these reactions with the potential to alter the pharmacokinetic profile or potency relative to the non-isotopic compound.

[80] According to embodiment (1), the present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, where:

ring Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L is selected from the connection, -(CR ^C0 R ^D0 ) _u -, -(CR ^C0 R ^D0 ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C (O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR _A0 S(O) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -;

X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N;

Y is selected from CR ⁴ and N;

R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -c( =nr ^e1 )r ^a1 , -c(=n-or ^b1 )r ^a1 , -C(O)OR ^A1 , -OC(O)R ^A1 , -С(O)NR ^A1 R ^B1 , -nr ^a1 (o )r ^b1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 (O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -s(o)(=nr ^e1 )r ^b1 , -n=s( o)r ^a1 r ^b1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1 ;

R ² is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X2 ;

R ³ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X3 ;

R ⁴ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A4 R ^B4 , -OR ^A4 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X4 ;

R ⁵ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 RB5, -OR ^A5 , -C(O)R ^A5 , -C(= NR ^E5 )R ^A5 , -c(=n-or ^b5 )r ^a5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C(O )R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S( O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ), where alkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 ;

each R ^A0 and R ^B0 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X0 ;

or each "R ^A0 and R ^B0 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X0 groups;

each R ^A1 and R ^B1 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1 ;

or each "R ^A1 and R ^B1 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X1 groups;

each R ^A2 and R ^B2 is independently selected from hydrogen, C _1-10 alkyl, C _1-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X2 ;

or each "R ^A2 and R ^B2 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X2 groups;

each R ^A3 and R ^B3 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X3 ;

or each "R ^A3 and R ^B3 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X3 groups;

each R ^A4 and R ^B4 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X4 ;

or each "R ^A4 and R ^B4 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X4 groups;

each R ^A5 and R ^B5 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 ;

or each "R ^A5 and R ^B5 ", together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R ^X5 groups;

each R ^C0 and R ^D0 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X0 ;

or R ^C0 and R ^D0 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^X0 groups;

each R ^E0 , R ^E1 and R ^E5 is independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -c(o)r ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ;

R ^X , R ^X' , R ^X0 , R ^X1 , R ^X2 , R ^X3 , R ^X4 and R ^X5 are each independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 -10} cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^el )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C (=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S (O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent independently selected from R ^Y ;

each R ^a1 and each R ^b1 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^e1 is independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -c(o)r ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ;

each r ^y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , - C(O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O) R ^a2 , -CN, -C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C (O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ), -C(=NR ^e2 )R ^a2 , -C(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1-10 alkylthio, C 3-10 cycloalkylthio} , C _1-10 alkylamino, C _3-10 cycloalkylamino and di( C _1-10 alkyl)amino;

each R ^a2 and each R ^b2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

or R ^a2 and R ^b2 , together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _{1-10 alkylthio, C 3-10 cycloalkylthio} , amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^c2 and R ^d2 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ;

each R is independently chosen from 0, 1, and 2;

each t is independently chosen from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3, and 4.

[81] According to another embodiment (2), the present invention relates to a compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ , the compound having a structure of formula (II)

where Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are defined in formula (I).

[82] According to another embodiment (3), the present invention relates to a compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Y is N.

[83] According to another embodiment (4), the present invention relates to a compound according to any one of embodiments (1) to (3), or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from C _3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[84] According to another embodiment (5), the present invention relates to a compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from wherein each is unsubstituted or substituted by at least one substituent independently selected from R ^X .

[85] According to another embodiment (6), the present invention relates to a compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from which are unsubstituted or substituted by at least one substituent independently selected from R ^X .

[86] According to another embodiment (7), the present invention relates to a compound according to any one of embodiments (1) to (6), or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X of ring Q is selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl and C _3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y .

[87] According to another embodiment (8), the present invention relates to a compound of embodiment (7) or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X of ring Q is selected from hydrogen, C _1-10 alkyl, C _2-10 alkynyl, wherein alkyl and alkynyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y .

[88] According to another embodiment (9), the present invention relates to a compound of embodiment (8) or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X of ring Q is selected from methyl and ethynyl, wherein the substituent R ^Y of methyl is F or OH.

[89] According to another embodiment (10), the present invention relates to a compound according to any one of embodiments (1) to (9), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from RX ¹ .

[90] According to another embodiment (11), the present invention relates to a compound of embodiment (10) or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RX ¹ .

[91] According to another embodiment (12), the present invention relates to a compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein the substituent RX ¹ of methyl is selected from OH, CN, NH ₂ ,

[92] According to another embodiment (13), the present invention relates to a compound according to any one of embodiments (1) to (12), or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from

[93] According to another embodiment (14), the present invention relates to a compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from

[94] According to another embodiment (15), the present invention relates to a compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from

[95] According to another embodiment (16), the present invention relates to a compound according to any one of embodiments (1) to (15), or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N, wherein R ^{X' is} independently selected from hydrogen, deuterium, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and -(CR ^c1 R ^d1 ) _t OR ^b1 .

[96] According to another embodiment (17), the present invention relates to a compound according to any one of embodiments (1) to (16), or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from

[97] According to another embodiment (18), the present invention relates to a compound of embodiment (17) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from

[98] According to another embodiment (19), the present invention relates to a compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) is selected from And

[99] According to another embodiment (20), the present invention relates to a compound according to any one of embodiments (16) to (19), or a pharmaceutically acceptable salt thereof, wherein R ^X' is selected from hydrogen, F, Cl, Br, CN, methyl, methoxy and cyclopropyl.

[100] According to another embodiment (21), the present invention relates to a compound of embodiment (20) or a pharmaceutically acceptable salt thereof, wherein R ^X' is selected from hydrogen, F, Cl and methyl.

[101] According to another embodiment (22), the present invention relates to a compound of embodiment (21) or a pharmaceutically acceptable salt thereof, wherein R ^X' is selected from hydrogen, F, Cl and methyl, preferably F or Cl, more preferably F.

[102] According to another embodiment (23), the present invention relates to a compound of embodiment (18) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) is selected from preferably a fragment selected from more preferably a fragment selected from most preferably a fragment selected from

[103] According to another embodiment (24), the present invention relates to a compound according to any one of embodiments (1) to (23), or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond, -(CR ^C0 R ^D0 ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, and -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -.

[104] According to another embodiment (25), the present invention relates to a compound of embodiment (24) or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond, -O-, -S- and -C(O)N( ^RA0 )-.

[105] According to another embodiment (26), the present invention relates to a compound of embodiment (25) or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond and -O-.

[106] According to another embodiment (27), the present invention relates to a compound of embodiment (26) or a pharmaceutically acceptable salt thereof, wherein L is -O-.

[107] According to another embodiment (28), the present invention relates to a compound according to any one of embodiments (1) to (27), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from halogen, C _1-10 alkyl, C _3-10 cycloalkyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 .

[108] According to another embodiment (29), the present invention relates to a compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from F, phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 .

[109] According to another embodiment (30), the present invention relates to a compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is phenyl, wherein each phenyl is unsubstituted or substituted with at least one substituent independently selected from R ^X5 .

[110] According to another embodiment (31), the present invention relates to a compound according to any one of embodiments (28) to (30), or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X5 is selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 and -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y .

[111] According to another embodiment (32), the present invention relates to a compound of embodiment (31) or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X5 is selected from halogen and methoxy.

[112] According to another embodiment (33), the present invention relates to a compound of embodiment (32) or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X5 is selected from halogen, preferably R ^X5 is F.

[113] According to another embodiment (34), the present invention relates to a compound of embodiment (32) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is phenyl, wherein each phenyl is unsubstituted or substituted by at least one substituent independently selected from F and methoxy, preferably each phenyl is unsubstituted or substituted by at least one substituent independently selected from F; or R ⁵ is pyridinyl, wherein pyridinyl is unsubstituted or substituted by at least one substituent independently selected from F.

[114] According to another embodiment (35), the present invention relates to a compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is pyridinyl and the pyridinyl is unsubstituted.

[115] According to another embodiment (36), the present invention relates to a compound according to any one of embodiments (1) to (35), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from F, phenyl,

[116] According to another embodiment (37), the present invention relates to a compound of embodiment (36) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl,

[117] According to another embodiment (38), the present invention relates to a compound of embodiment (37) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from

[118] According to another embodiment (39), the present invention relates to a compound of embodiment (23) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) is selected from And more preferably a fragment selected from most preferably fragment selected from

[119] According to another embodiment (40), the present invention relates to a compound according to any one of embodiments (1) to (39), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, halogen, C _1-10 alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

[120] According to another embodiment (41), the present invention relates to a compound of embodiment (40) or a pharmaceutically acceptable salt thereof, wherein R ^A2 -OR ^A2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl and C _3-10 cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from RX ² .

[121] According to another embodiment (42), the present invention relates to a compound according to any one of embodiments (40) to (41), or a pharmaceutically acceptable salt thereof, wherein RX ² is selected from deuterium and halogen.

[122] According to another embodiment (43), the present invention relates to a compound according to any one of embodiments (1) to (42), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methyl, ethyl, methoxy, ethoxy, -C(O)NH ₂ , CN, OH,

[123] According to another embodiment (44), the present invention relates to a compound of embodiment (43) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, CN, methoxy and ethoxy.

[124] According to another embodiment (45), the present invention relates to a compound of embodiment (44) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, CN, methoxy and ethoxy.

[125] According to another embodiment (46), the present invention relates to a compound of embodiment (45) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, methoxy and ethoxy.

[126] According to another embodiment (47), the present invention relates to a compound of embodiment (46) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from methoxy and ethoxy.

[127] According to another embodiment (48), the present invention relates to a compound according to any one of embodiments (1) to (47), or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, C _1-10 alkyl, and halogen.

[128] According to another embodiment (49), the present invention relates to a compound of embodiment (48) or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

[129] According to another embodiment (50), the present invention relates to a compound of embodiment (48) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

[130] According to another embodiment (51), the present invention relates to a compound selected from

and its pharmaceutically acceptable salts.

[131] According to another embodiment (52), the present invention relates to a pharmaceutical composition comprising a compound according to any one of embodiments (1) to (51) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[132] According to another embodiment (53), the present invention relates to a method of treating, alleviating or preventing a condition that responds to inhibition of BTK, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments (1) to (51), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[133] According to another embodiment (54), the present invention relates to the use of a compound according to any one of embodiments (1) to (51) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a cell proliferative disorder.

[134] Some embodiments may also be described as follows:

[135] According to another embodiment <1> the present invention relates to a compound of formula <I'>

or a pharmaceutically acceptable salt thereof, where:

ring Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L is selected from the connection, -(CR ^C0 R ^D0 ) _u -, -(CR ^C0 R ^D0 ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C (O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -;

X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N;

R ¹ is selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , - C(=NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O)OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C(O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N =S(O)R ^A1 R ^B1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ² is selected from hydrogen, deuterium, halogen, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ³ is selected from hydrogen, deuterium, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁴ is selected from hydrogen, deuterium, halogen, CN, NO ₂ , -NR ^A4 R ^B4 , -OR ^A4 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁵ is selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O)R ^A5 , - C(=NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C(O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N =S(O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , R ^B2 , R ^B3 , R ^B4 and R ^B5 is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

or each "R ^A0 and R ^B0 ,""R ^A1 and R ^B1 ,""R ^A2 and R ^B2 ,""R ^A3 and R ^B3 ,""R ^A4 and R ^B4 ," or "R ^A5 and R ^B5 ," together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and optionally substituted with 1, 2, or 3 R ^X groups;

each R ^C0 and R ^D0 is independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

or R ^C0 and R ^D0 , together with the carbon atom(s) to which they are attached, form a ring of 3-12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^X groups;

each R ^E0 , R ^E1 and R ^E5 is independently selected from hydrogen, deuterium, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ;

each R ^X is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl- C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(= N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C( =NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S( O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted by at least one substituent, independently selected from R ^Y ;

each R ^a1 and each R ^b1 is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a ring of 3-12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^e1 is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ;

each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 ,-(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C (O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, - C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ), -C(=NR ^e2 )R ^a2 , -С(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C( =NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl )amino;

each R ^a2 and each R ^b2 is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^a2 and R ^b2 , together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 is independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C _1-4 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

or R ^c2 and R ^d2 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^e2 is independently selected from hydrogen, deuterium, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ;

each R is independently chosen from 0, 1, and 2;

each t is independently chosen from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3, and 4.

[136] According to another embodiment <2>, the present invention relates to a compound of embodiment <1> or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from C _3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[137] According to another embodiment <3>, the present invention relates to a compound of embodiment <2> or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from cyclohexyl and tetrahydropyran, wherein cyclohexyl and tetrahydropyran are unsubstituted or substituted with at least one substituent independently selected from R ^X .

[138] According to another embodiment <4>, the present invention relates to a compound according to any one of embodiments <1> to <3>, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[139] According to another embodiment <5>, the present invention relates to a compound of embodiment <4> or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[140] According to another embodiment <6>, the present invention relates to a compound of embodiment <5> or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein methyl is substituted with R ^X .

[141] According to another embodiment <7>, the present invention relates to a compound of embodiment <6> or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein methyl is substituted with OH.

[142] According to another embodiment <8>, the present invention relates to a compound according to any one of embodiments <1> to <7>, or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ and X ⁴ are CR ^X , wherein R ^X is independently selected from hydrogen, deuterium, halogen, CN and C _1-10 alkyl.

[143] According to another embodiment <9>, the present invention relates to a compound of embodiment <8> or a pharmaceutically acceptable salt thereof, wherein the substructure of formula <II'> in the formula <I'> represents

[144] According to another embodiment <10>, the present invention relates to a compound of embodiment <9> or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from hydrogen, F, Cl, CN and methyl.

[145] According to another embodiment <11>, the present invention relates to a compound according to any one of embodiments <1> to <10>, or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR ^C1 R ^D1 ) _u O(CR ^C1 R ^D1 ) _t -, -(CR ^C1 R ^D1 ) _u S(CR ^C1 R ^D1 ) _t -, and -(CR ^C1 R ^D1 ) _u C(O)NR ^A1 (CR ^C1 R ^D1 ) _t -.

[146] According to another embodiment <12>, the present invention relates to a compound of embodiment <11> or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

[147] According to another embodiment <13>, the present invention relates to a compound of embodiment <12> or a pharmaceutically acceptable salt thereof, wherein L is -O-.

[148] According to another embodiment <14>, the present invention relates to a compound according to any one of embodiments <1> to <13>, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[149] According to another embodiment <15>, the present invention relates to a compound of embodiment <14> or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl, wherein aryl is unsubstituted or substituted with R ^X .

[150] According to another embodiment <16>, the present invention relates to a compound of embodiment <15> or a pharmaceutically acceptable salt thereof, wherein phenyl is unsubstituted or substituted with halogen.

[151] According to another embodiment <17>, the present invention relates to a compound according to any one of embodiments <1> to <16>, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, deuterium, halogen, C _1-10 alkyl and CN.

[152] According to another embodiment <18>, the present invention relates to a compound of embodiment <17> or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F and CN.

[153] According to another embodiment <19>, the present invention relates to a compound according to any one of embodiments <1> to <18>, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, deuterium, C _1-10 alkyl and halogen.

[154] According to another embodiment <20>, the present invention relates to a compound of embodiment <19> or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

[155] According to another embodiment <21>, the present invention relates to a compound of embodiment <19> or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

[156] According to another embodiment <22>, the present invention relates to a pharmaceutical composition comprising a compound according to any one of embodiments <1> to <21> or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[157] According to another embodiment <23> the present invention relates to a method of treating, alleviating or preventing a condition that responds to inhibition of BTK, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments <1> to <21> or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[158] According to another embodiment <24> the present invention relates to the use of a compound according to any one of embodiments <1> to <21> or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a cell proliferative disorder.

[159] Some embodiments may also be described as follows:

[160] According to another embodiment [1], the present invention relates to a compound of formula [I'']

or a pharmaceutically acceptable salt thereof, where:

ring Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L is selected from the connection, -(CR ^C0 R ^D0 ) _u -, -(CR ^C0 R ^D0 ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C (O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 ) _t -;

X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N;

Y is selected from CR ⁴ and N;

R ¹ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C( =NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O)OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C( O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR ^A1 R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S (O)R ^A1 R ^B1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ² is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ³ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁴ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A4 R ^B4 , -OR ^A4 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁵ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O)R ^A5 , -C( =NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C( O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O) _r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S (O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , R ^B2 , R ^B3 , R ^B4 and R ^B5 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

or each "R ^A0 and R ^B0 ,""R ^A1 and R ^B1 ,""R ^A2 and R ^B2 ,""R ^A3 and R ^B3 ,""R ^A4 and R ^B4 ," or "R ^A5 and R ^B5 ," together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and optionally substituted with 1, 2, or 3 R ^X groups;

each R ^C0 and R ^D0 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

or R ^C0 and R ^D0 , together with the carbon atom(s) to which they are attached, form a ring of 3-12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^X groups;

each R ^E0 , R ^E1 and R ^E5 is independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ;

each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 ) _t NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(=N- OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(= NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 ,-(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^e1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 )P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from each R ^a1 and each R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a ring of 3-12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^e1 is independently selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ;

each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C (O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, - C(O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , -NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ), -C(=NR ^e2 )R ^a2 , -С(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C( =NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl )amino;

each R ^a2 and each R ^b2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl _, C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^a2 and R ^b2 , together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^c2 and each R ^d2 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^c2 and R ^d2 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ;

each R is independently chosen from 0, 1, and 2;

each t is independently chosen from 0, 1, 2, 3, and 4;

each u is independently chosen from 0, 1, 2, 3, and 4.

[161] According to another embodiment [2], the present invention relates to a compound of embodiment [1] or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ , the compound having the formula [II'']

where Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are defined in formula [I''].

[162] According to another embodiment [3], the present invention relates to a compound according to any one of embodiments [1]-[2], or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from C _3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[163] According to another embodiment [4], the present invention relates to a compound of embodiment [3] or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from which are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[164] According to another embodiment [5], the present invention relates to a compound according to any one of embodiments [1] to [4], or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C _1-10 alkyl and C _3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[165] According to another embodiment [6], the present invention relates to a compound of embodiment [5] or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X .

[166] According to another embodiment [7], the present invention relates to a compound of embodiment [6] or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein methyl is substituted with OH, CN and

[167] According to another embodiment [8], the present invention relates to a compound according to any one of embodiments [1] to [7], or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ and X ⁴ are CR ^X , and X ³ is selected from CR ^X and N, wherein R ^X is independently selected from hydrogen, deuterium, halogen, CN and C _1-10 alkyl.

[168] According to another embodiment [9], the present invention relates to a compound according to any one of embodiments [1] to [8], or a pharmaceutically acceptable salt thereof, wherein the substructure of formula [III''] in formula [I''] or formula [II''] is selected from

[169] According to another embodiment [10], the present invention relates to a compound of embodiment [9] or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from hydrogen, F, Cl, CN and methyl.

[170] According to another embodiment [11], the present invention relates to a compound according to any one of embodiments [1] to [10], or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR ^C1 R ^D1 ) _u O(CR ^C1 R ^D1 ) _t -, -(CR ^C1 R ^D1 ) _u S(CR ^C1 R ^D1 ) _t -, and -(CR ^C1 R ^D1 ) _u C(O)NR ^A1 (CR ^C1 R ^D1 ) _t -.

[171] According to another embodiment [12], the present invention relates to a compound of embodiment [11] or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

[172] According to another embodiment [13], the present invention relates to a compound of embodiment [12] or a pharmaceutically acceptable salt thereof, wherein L is -O-.

[173] According to another embodiment [14], the present invention relates to a compound according to any one of embodiments [1] to [13], or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[174] According to another embodiment [15], the present invention relates to a compound of embodiment [14] or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with R ^X .

[175] According to another embodiment [16], the present invention relates to a compound of embodiment [15] or a pharmaceutically acceptable salt thereof, wherein R ^X is halogen.

[176] According to another embodiment [17], the present invention relates to a compound according to any one of embodiments [1] to [16], or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, halogen, C _1-10 alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

[177] According to another embodiment [18], the present invention relates to a compound of embodiment [17] or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methyl, methoxy, -C(O)NH ₂ and CN.

[178] According to another embodiment [19], the present invention relates to a compound according to any one of embodiments [1] to [18] or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, C _1-10 alkyl and halogen.

[179] According to another embodiment [20], the present invention relates to a compound of embodiment [19] or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

[180] According to another embodiment [21], the present invention relates to a compound of embodiment [19] or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

[181] According to another embodiment [22], the present invention relates to a pharmaceutical composition comprising a compound according to any one of embodiments [1] to [21] or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[182] According to another embodiment [23], the present invention relates to a method of treating, alleviating or preventing a condition that responds to inhibition of BTK, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments [1] to [21], or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[183] According to another embodiment [24], the present invention relates to the use of a compound according to any one of embodiments [1] [21] or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a cell proliferative disorder.

[184] Some embodiments may also be described as follows:

[185] According to another embodiment (i), the present invention relates to a compound of formula (I''')

or a pharmaceutically acceptable salt thereof, where:

ring Q is selected from C _3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

L is selected from the connection, -(CR ^C0 R ^D0 ) _u -, -(CR ^C0 R ^D0 ) _u O(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(=NR ^E0 )(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u C(O)NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C(O)(CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 C (O)NR ^B0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u S(O) _r NR ^A0 (CR ^C0 R ^D0 ) _t -, -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r (CR ^C0 R ^D0 ) _t - and -(CR ^C0 R ^D0 ) _u NR ^A0 S(O) _r NR ^B0 (CR ^C0 R ^D0 )t-;

X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X and N;

Y is selected from CR ⁴ and N;

R ¹ is selected from hydrogen, halogen, C ^1-10 alkyl, C ^2-10 alkenyl, C ^2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A1 R ^B1 , -OR ^A1 , -C(O)R ^A1 , -C( =NR ^E1 )R ^A1 , -C(=N-OR ^B1 )R ^A1 , -C(O)OR ^A1 , -OC(O)R ^A1 , -C(O)NR ^A1 R ^B1 , -NR ^A1 C( O)R ^B1 , -C(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )R ^B1 , -OC(O)NR ^A1 R ^B1 , -NR ^A1 C(O)OR ^B1 , -NR ^A1 C(O)NR ^A1 R ^B1 , -NR ^A1 C(S)NR ^A1 R ^B1 , -NR ^A1 C(=NR ^E1 )NR R ^B1 , -S(O) _r R ^A1 , -S(O)(=NR ^E1 )R ^B1 , -N=S( O)R ^A1 R ^B1 , -S(O) ₂ OR ^A1 , -OS(O) ₂ R ^A1 , -NR ^A1 S(O) _r R ^B1 , -NR ^A1 S(O)(=NR ^E1 )R ^B1 , -S(O) _r NR ^A1 R ^B1 , -S(O)(=NR ^E1 )NR ^A1 R ^B1 , -NR ^A1 S(O) ₂ NR ^A1 R ^B1 , -NR ^A1 S(O)(=NR ^E1 )NR ^A1 R ^B1 , -P(O)R ^A1 R ^B1 and -P(O)(OR ^A1 )(OR ^B1 ), where alkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ² is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A2 R ^B2 , -OR ^A2 , -C(O)NR ^A2 R ^B2 , C ^1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ³ is selected from hydrogen, halogen, CN, NO ₂ , -NR ^A3 R ^B3 , -OR ^A3 , -C(O)NR ^A2 R ^B2 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁴ is selected from hydrogen, halogen, CN, NO2, -NR ^A4 R ^B4 , -OR ^A4 , C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X ;

R ⁵ is selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, CN, NO ₂ , -NR ^A5 R ^B5 , -OR ^A5 , -C(O)R ^A5 , -C( =NR ^E5 )R ^A5 , -C(=N-OR ^B5 )R ^A5 , -C(O)OR ^A5 , -OC(O)R ^A5 , -C(O)NR ^A5 R ^B5 , -NR ^A5 C( O)R ^B5 , -C(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )R ^B5 , -OC(O)NR ^A5 R ^B5 , -NR ^A5 C(O)OR ^B5 , -NR ^A5 C(O)NR ^A5 R ^B5 , -NR ^A5 C(S)NR ^A5 R ^B5 , -NR ^A5 C(=NR ^E5 )NR ^A5 R ^B5 , -S(O _)r R ^A5 , -S(O)(=NR ^E5 )R ^B5 , -N=S (O)R ^A5 R ^B5 , -S(O) ₂ OR ^A5 , -OS(O) ₂ R ^A5 , -NR ^A5 S(O) _r R ^B5 , -NR ^A5 S(O)(=NR ^E5 )R ^B5 , -S(O) _r NR ^A5 R ^B5 , -S(O)(=NR ^E5 )NR ^A5 R ^B5 , -NR ^A5 S(O) ₂ NR ^A5 R ^B5 , -NR ^A5 S(O)(=NR ^E5 )NR ^A5 R ^B5 , -P(O)R ^A5 R ^B5 and -P(O)(OR ^A5 )(OR ^B5 ) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from Rx;

each R ^A0 , R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^B0 , R ^B1 , R ^B2 , R ^B3 , R ^B4 and R ^B5 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X ;

or each "R ^A0 and R ^B0 ,""R ^A1 and R ^B1 ,""R ^A2 and R ^B2 ,""R ^A3 and R ^B3 ,""R ^A4 and R ^B4 ," or "R ^A5 and R ^B5 ," together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and optionally substituted with 1, 2, or 3 R ^X groups;

each R ^C0 and R ^D0 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from Rx;

or R ^C0 and R ^D0 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^X groups;

each R ^E0 , R ^E1 and R ^E5 is independently selected from hydrogen, C _1-10 alkyl, CN, NO ₂ , -OR ^a1 , -SR ^a1 , -S(O) _r R ^a1 , -C(O)R ^a1 , -C(O)OR ^a1 , -C(O)NR ^a1 R ^b1 and -S(O) _r NR ^a1 R ^b1 ;

each R ^X is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _{1 -4} alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, NO ₂ , -(CR ^c1 R ^d1 )tNR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t OR ^b1 , -(CR ^c1 R ^d1 ) _t C(O)R ^a1 , -(CR ^c1 R ^d1 ) ^t C(=NR ^d1 )R ^a1 , -(CR ^c1 R ^d1 )tC(=N-OR ^b1 )R ^a1 , -(CR ^c1 R ^d1 ) _t C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)R ^b1 , -(CR ^c1 R ^d1 ) _t C(O)NR ^a1 R ^b1 , - (CR ^c1 R ^d1 )tNR ^a1 C(0)R ^b1 , -(CR ^c1 R ^d1 ) _t C(=NR ^d1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^d1 ) R ^b1 , -(CR ^c1 R ^d1 ) _t OC(O)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O)OR ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(O )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(S)NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 C(=NR ^d1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^d1 )R ^b1 , -(CR ^c1 R ^d1 ) _t N=S(O)R ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S( O) ₂ OR ^b1 , -(CR ^c1 R ^d1 ) _t OS(O) ₂ R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) _r R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^d1 )R ^b1 , -(CR ^c1 R ^d1 ) _t S(O) _r NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t S(O)(=NR ^d1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O) ₂ NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t NR ^a1 S(O)(=NR ^d1 )NR ^a1 R ^b1 , -(CR ^c1 R ^d1 ) _t P(O)R ^a1 R ^b1 and -(CR ^c1 R ^d1 ) _t P(O)(OR ^a1 )(OR ^b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from

each R ^a1 and each R ^b1 is independently selected from hydrogen, C 2-10 alkyl, C _{2-10 alkenyl, C 2-10} alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y ;

or R ^a1 and R ^b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^c1 and each R ^d1 is independently selected from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from

or R ^c1 and R ^d1 together with the carbon atom(s) to which they are attached form a ring of 3-12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R ^Y groups;

each R ^d1 is independently selected from hydrogen, C 2 O alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂ , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -C(O)R ^a2 , -C(O)OR ^a2 , -S(O) _r NR ^a2 R ^b2 and -C(O)NR ^a2 R ^b2 ;

each R ^Y is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-Cm alkyl, aryl , aryl-C _1-4 alkyl, heteroaryl, heteroaryl-C _1-4 alkyl, halogen, CN, -NO ₂ , -NR ^a2 R ^b2 , -OR ^a2 , -SR ^a2 , -S(O) _r R ^a2 , -S(O) ₂ OR ^a2 , -OS(O) ₂ R ^b2 , -S(O) _r NR ^a2 R ^b2 , -P(O)R ^a2 R ^b2 , -P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t SR ^b2 , -(CR ^c2 R ^d2 ) _t S(O) _r R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)R ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t P(O)(OR ^a2 )(OR ^b2 ), -(CR ^c2 R ^d2 ) _t CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 )tNR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t OC(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)NR ^a2 R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -O(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -S(O) _r (CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C( O)R ^a2 , -C(O)(CR ^c2 R ^d2 ) _t OR ^b2 , -C(O)(CR ^c2 R ^d2 ) _t NR ^a2 R ^b2 , -C(O)(CR ^c2 R ^d2 ) _t SR ^b2 , -C(O)(CR ^c2 R ^d2 )_S(O) _r R ^b2 , -CO ₂ R ^b2 , -CO ₂ (CR ^c2 R ^d2 ) _t C(O)NR ^a2 R ^b2 , -OC(O)R ^a2 , -CN, -C( O)NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -OC(O)NR ^a2 R ^b2 , -NR ^a2 C(O)OR ^b2 , -NR ^a2 C(O)NR ^a2 R ^b2 , - NR ^a2 S(O) _r R ^b2 , -CR ^a2 (=N-OR ^b2 ), -C(=NR ^e2 )R ^a2 , - С(=NR ^e2 )NR ^a2 R ^b2 , -NR ^a2 C(=NR ^e2 )NR ^a2 R ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ , where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl , C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl )amino;

each R ^a2 and each R ^b2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di(C _1-10 alkyl)amino, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl _, C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^a2 and R ^b2 , together with the atom(s) to which they are attached, form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each Rc2 and each ^Rd2 is independently selected from hydrogen, halogen, _C1-10 alkyl, C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, _C3-10 cycloalkyl- _C1-4 alkyl _{, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino , C3-10 cycloalkylamino ,} di( _C1-10 alkyl)amino, heterocyclyl, heterocyclyl- _C1-4 alkyl, aryl, aryl- _C1-4 alkyl, _heteroaryl and heteroaryl- _C1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 cycloalkyl, OH, _C1-10 alkoxy, _C3-10 cycloalkoxy, _C1-10 alkylthio, _C3-10 cycloalkylthio, amino, _C1-10 alkylamino, _C3-10 cycloalkylamino and di( _C1-10 alkyl)amino;

or R ^c2 and R ^d2 , together with the carbon atom(s) to which they are attached, form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di(C _1-10 alkyl)amino;

each R ^e2 is independently selected from hydrogen, CN, NO ₂ , C _1-10 alkyl, C _3-10 cycloalkyl, C 3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C(O)C _1-4 alkyl, -C(O)C _3-10 cycloalkyl, -C(O)OC _1-4 alkyl, -C(O)OC _3-10 cycloalkyl, -C(O)N(C _1-4 alkyl)2, -C(O)N(C _3-10 cycloalkyl) ₂ , -S(O) ₂ C _1-4 alkyl, -S(O) ₂ C _3-10 cycloalkyl, -S(O) ₂ N(C _1-4 alkyl) ₂ and -S(O) ₂ N(C _3-10 cycloalkyl) ₂ ;

each R is independently chosen from 0, 1, and 2;

each t is independently chosen from 0, 1, 2, 3, and 4;

each independently selected from 0, 1, 2, 3, and 4.

[186] According to another embodiment (ii), the present invention relates to a compound of embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Y is CR ⁴ , the compound having the formula (II''')

where Q, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and X ⁴ are defined in formula (I''').

[187] According to another embodiment (iii), the present invention relates to a compound according to any one of embodiments (i) to (ii), or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from C _3-10 cycloalkyl and heterocyclyl, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[188] According to another embodiment (iv), the present invention relates to a compound of embodiment (iii) or a pharmaceutically acceptable salt thereof, wherein ring Q is selected from which are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[189] According to another embodiment (v), the present invention relates to a compound according to any one of embodiments (i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C ^1-10 alkyl and C ^3-10 cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[190] According to another embodiment (vi), the present invention relates to a compound of embodiment (v) or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from Rx ^X

[191] According to another embodiment (vii), the present invention relates to a compound of embodiment (vi) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein methyl is substituted with OH, CN and

[192] According to another embodiment (viii), the present invention relates to a compound according to any one of embodiments (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ and X4 are independently selected from CR ^X and N, wherein R ^X is independently selected from hydrogen, deuterium, halogen, CN, C _1-10 alkyl, C _3-10 cycloalkyl and -(CR ^c1 R ^d1 ) _t OR ^b1 .

[193] According to another embodiment (ix), the present invention relates to a compound according to any one of embodiments (i) to (viii), or a pharmaceutically acceptable salt thereof, wherein the substructure of formula (III''') in formula (I''') or formula (II''') is selected from

[194] According to another embodiment (x), the present invention relates to a compound of embodiment (ix) or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from hydrogen, F, Cl, Br, CN, methyl, methoxy and cyclopropyl.

[195] According to another embodiment (xi), the present invention relates to a compound according to any one of embodiments (i) to (x), or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR ^c1 R ^D1 ) _u O(CR ^c1 R ^D1 ) _t -, -(CR ^c1 R ^D1 ) _u S(CR ^c1 R ^D1 ) _t - and -(CR ^c1 R ^D1 ) _u C(O)NR ^A1 (CR ^c1 R ^D1 ) _t -.

[196] According to another embodiment (xii), the present invention relates to a compound of embodiment (xi) or a pharmaceutically acceptable salt thereof, wherein L is selected from -O-, -S- and -C(O)N(R ^A1 )-.

[197] According to another embodiment (xiii), the present invention relates to a compound of embodiment (xii) or a pharmaceutically acceptable salt thereof, wherein L is -O-.

[198] According to another embodiment (xiv), the present invention relates to a compound according to any one of embodiments (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[199] According to another embodiment (xv), the present invention relates to a compound of embodiment (xiv) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with R ^X .

[200] According to another embodiment (xvi), the present invention relates to a compound of embodiment (xv) or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from halogen and methoxy.

[201] According to another embodiment (xvii), the present invention relates to a compound according to any one of embodiments (i) to (xvi), or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from hydrogen, halogen, C _1-10 alkyl, -OR ^A2 , -C(O)NR ^A2 R ^B2 and CN.

[202] According to another embodiment (xviii), the present invention relates to a compound of embodiment (xvii) or a pharmaceutically acceptable salt thereof, wherein R ^A2 -OR ^A2 is independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl and C _3-10 cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X .

[203] According to another embodiment (xix), the present invention relates to a compound according to any one of embodiments (xvii) to (xviii), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methyl, ethyl, methoxy,

ethoxy, -C(O)NH ₂ , CN, OH,

[204] According to another embodiment (xx), the present invention relates to a compound according to any one of embodiments (i) to (xix), or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are independently selected from hydrogen, C _1-10 alkyl, and halogen.

[205] According to another embodiment (xxi), the present invention relates to a compound of embodiment (xx) or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

[206] According to another embodiment (xxii), the present invention relates to a compound of embodiment (xxi) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

[207] According to another embodiment (xxiii), the present invention relates to a pharmaceutical composition comprising a compound according to any one of embodiments (i) to (xxii) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[208] According to another embodiment (xxiv), the present invention relates to a method of treating, alleviating or preventing a condition that responds to inhibition of BTK, the method comprising administering to a subject in need of such treatment an effective amount of a compound of any one of embodiments (i) to (xxii), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[209] According to another embodiment (xxv), the present invention relates to the use of a compound according to any one of embodiments (i) to (xxii), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a cell proliferative disorder.

[210] According to another aspect, there is provided a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and instructions that comprise one or more forms of information selected from the group consisting of an indication of the pathological condition for which the composition is to be administered, information on storing the composition, information on administering a dose, and instructions on how to administer the composition. According to one particular variation, the kit comprises the compound in multiple dosage form.

[211] According to another aspect, there is provided an article of manufacture comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and packaging materials. According to one variation, the packaging material comprises a container for containing the compound. According to one particular variation, the container comprises a label indicating one or more members of the group consisting of a pathological condition for which the compound is to be administered, storage information, dosing information, and/or instructions regarding how to administer the compound. According to another variation, the article of manufacture comprises the compound in multiple dosage form.

[212] According to a further aspect, a therapeutic method is provided comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[213] According to another aspect, there is provided a method of inhibiting BTK kinase comprising contacting BTK with a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[214] According to yet another aspect, there is provided a method of inhibiting VTK comprising providing the presence of a compound disclosed herein or a pharmaceutically acceptable salt thereof in the body of a subject to inhibit VTK in vivo.

[215] According to a further aspect, there is provided a method of inhibiting BTK, comprising administering a first compound to a subject that is converted in vivo to a second compound, wherein the second compound inhibits BTK in vivo, wherein the second compound is a compound according to any of the above embodiments and variations.

[216] According to another aspect, there is provided a method of treating a pathological condition in which the VTC has an activity that contributes to the pathology and/or symptomatology of the pathological condition, the method comprising providing the presence of a compound disclosed herein or a pharmaceutically acceptable salt thereof in a subject in a therapeutically effective amount for the pathological condition.

[217] According to a further aspect, there is provided a method of treating a pathological condition in which the BTK has an activity that contributes to the pathology and/or symptomology of the pathological condition, wherein the method comprises administering a first compound to a subject that is converted in vivo to a second compound, wherein the second compound inhibits the BTK in vivo. It should be noted that the compounds of the present invention can be the first or second compounds.

[218] According to one variation of each of the above methods, the pathological condition is selected from the group consisting of malignant hyperproliferative disorders (e.g., brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, excretory system cancer, kidney cancer, ovarian cancer, prostate cancer, colorectal cancer, epidermoid cancer, esophageal cancer, testicular cancer, gynecologic cancer, or thyroid cancer); benign hyperproliferative disorders (e.g., benign hyperplasia of the skin (e.g., psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; prevention of blastocyte implantation; treatment of diseases associated with vasculogenesis or angiogenesis (e.g. tumour angiogenesis, acute and chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and cancers of the ovary, breast, lung, pancreas, prostate, colon and epidermoid cancer); asthma; neutrophil chemotaxis (e.g. reperfusion injury in myocardial infarction and stroke and inflammatory arthritis); septic shock; T-cell-mediated diseases in which immune suppression may be important (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; suppression of the keratinocyte response to growth factor cocktails; chronic obstructive pulmonary disease (COPD), and other diseases.

[219] According to another aspect, a method of treating a pathological condition is provided in which a mutation in the BTK gene contributes to the pathology and/or symptomatology of the pathological condition, including, for example, melanomas, lung cancer, colon cancer and other types of tumors.

[220] According to another aspect, the present invention relates to the use of a compound of any of the above embodiments and variations as a medicament. According to another aspect, the present invention relates to the use of a compound of any of the above embodiments and variations in the manufacture of a medicament for inhibiting BTK.

[221] According to a further aspect, the present invention relates to the use of a compound according to any of the above embodiments and variations in the manufacture of a medicament for the treatment of a pathological condition in which the BTC has an activity that contributes to the pathology and/or symptomatology of the pathological condition.

Introduction and pharmaceutical compositions

[222] In general, the compounds of the present disclosure will be administered in therapeutically effective amounts by any of the usual and appropriate routes known in the art, either alone or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and underlying health of the subject, the potency of the compound being used, and other factors known to those of ordinary skill in the art. For example, for the treatment of neoplastic diseases and immune system disorders, the necessary dosage will also vary depending on the route of administration, the particular condition being treated, and the desired effect.

[223] In general, satisfactory results are shown to be obtained systemically at daily dosages of from about 0.001 to about 100 mg/kg body weight, or in particular from about 0.03 to 2.5 mg/kg body weight. The prescribed daily dosage for a larger mammal, such as humans, may be in the range of from about 0.5 mg to about 2000 mg, or more in particular from about 0.5 mg to about 1000 mg, which is usually administered, for example, in divided doses, up to four times daily or in sustained-release form. Suitable unit dosage forms for oral administration contain from about 1 to 50 mg of the active ingredient.

[224] The compounds of the present disclosure may be administered as pharmaceutical compositions by any convenient route; for example, enterally, for example orally, for example in the form of tablets or capsules; parenterally, for example in the form of injectable solutions or suspensions; or topically, for example in the form of lotions, gels, ointments or creams, or in nasal form or in suppository form.

[225] Pharmaceutical compositions comprising a compound according to the present disclosure in free form or in the form of a pharmaceutically acceptable salt in association with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound according to the present disclosure in association with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.

Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.

[226] According to one embodiment, the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. In the case of lyophilized compositions containing the active ingredient alone or together with a carrier such as mannitol, the dispersions or suspensions can be prepared before use. The pharmaceutical compositions can be sterilized and/or can contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, solution accelerators, salts for adjusting the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid or microbiocides such as sorbic acid or benzoic acid. Solutions or suspensions may additionally contain viscosity enhancing agents, including but not limited to sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins or solubilizers such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[227] Oil suspensions may contain vegetable, synthetic or semi-synthetic oils commonly used for injections as an oil component. Examples include, but are not limited to, liquid fatty acid esters that contain, as an acid component, a long-chain fatty acid having 8-22 carbon atoms, or in some embodiments 12-22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated acids such as oleic acid, elaidic acid, erucic acid, brassidic acid, and linoleic acid, and may optionally contain antioxidants such as vitamin E, 3-carotene, or 3,5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as a mono-, di-, or trivalent alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof; glycol and glycerin.

[228] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M 2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturated polyglycolized glycerides obtained by alcoholysis of apricot kernel oil and containing glycerides and a polyethylene glycol ester), LABRASOL™ (saturated polyglycolized glycerides obtained by alcoholysis of TCM and containing glycerides and a polyethylene glycol ester; all available from GaKefosse, France) and/or MIGLYOL® 812 (a triglyceride of saturated fatty acids with a chain length of C8-C12 from Hiils AG, Germany), as well as vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

[229] Pharmaceutical compositions for oral administration can be prepared, for example, by combining the active ingredient with one or more solid carriers and, if necessary, granulating the resulting mixture, and processing the mixture or granules by incorporating additional auxiliaries to form tablets or tablet cores.

[230] Suitable carriers include, but are not limited to, fillers such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose,

sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if necessary, disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof such as sodium alginate. Additional auxiliaries include, but are not limited to, flow conditioners and lubricants such as silicic acid, talc, stearic acid or their salts such as magnesium or calcium stearate, and/or polyethyleneglycol or their derivatives.

[231] The tablet cores may be provided with suitable, optionally enteric, coatings using, inter alia, concentrated solutions of sugars which may include acacia, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient.

[232] Pharmaceutical compositions for oral administration may also include hard capsules containing gelatin or soft sealed capsules containing gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oil, or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and disintegrants, for example polyoxyethylene ester of sorbitol and fatty acid, may also be added.

[233] Pharmaceutical compositions suitable for rectal administration are, for example, suppositories containing a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols.

[234] Pharmaceutical compositions suitable for parenteral administration may comprise aqueous solutions of the active ingredient in water-soluble form, for example a water-soluble salt, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, if desired, stabilizers. The active ingredient, optionally together with excipients, may also be in the form of a lyophilisate and can be converted into solution before parenteral administration by the addition of suitable solvents. Solutions such as those used, for example, for parenteral administration may also be used as infusion solutions. The manufacture of injectable preparations is generally carried out under sterile conditions, as is the filling of, for example, ampoules or vials, and the sealing of containers.

[235] The present disclosure also relates to pharmaceutical combinations, such as a kit, comprising a) a first agent that is a compound of the present disclosure, as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-administered agent. The kit may contain instructions for its administration.

Combination therapies

[236] The compounds or pharmaceutically acceptable salts of the present disclosure may be administered as monotherapy or in combination with another therapeutic agent or agents.

[237] For example, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an excipient (i.e., the excipient may have only minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Otherwise, by way of example only, the benefit experienced by an individual may be enhanced by administering one of the compounds described herein with another therapeutic agent that also has therapeutic benefit. By way of example only, in a treatment for gout involving the administration of one of the compounds described herein, enhanced therapeutic benefit may result from also providing the individual with another therapeutic agent for gout. Otherwise, by way of example only, if one of the side effects experienced by an individual when taking one of the compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with that compound. Otherwise, additional therapy or therapies include, but are not limited to, physical therapy, psychotherapy, radiation therapy, application of compresses to the affected area, rest, dietary changes, etc. Regardless of the disease, disorder, or condition being treated, the overall benefit received by an individual may be the sum of the two therapies, or the individual may experience a synergistic effect.

[238] In cases where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein may be administered in the same pharmaceutical composition as the other therapeutic agents or, due to different physical and chemical characteristics, administered by a different route. For example, the compounds described herein may be administered orally to create and maintain high blood levels while another therapeutic agent may be administered intravenously. Thus, the compounds described herein may be administered simultaneously, sequentially, or separately with other therapeutic agents.

EXAMPLES

[239] Various methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be developed. Typical methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the examples. However, it should be noted that the compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that may be developed by others.

[240] It is readily appreciated that some compounds of formula (I) have atoms in bonds with other atoms that impart a particular stereochemistry to the compound (e.g., chiral centers). It is known that the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). If a particular stereochemistry is not specified, reference to a compound is intended to cover all the various possible stereoisomers.

[241] A compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting the free base form of at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of at least one compound of formula (I) can be prepared, for example, by reacting the free acid form of at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula (I) are set forth in the Definitions section of the present application. Alternatively, salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

[242] The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in the form of an acid addition salt can be converted into its corresponding free base by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A compound of formula (I) in the form of a base addition salt can be converted into its corresponding free acid by, for example, treatment with a suitable acid (e.g., hydrochloric acid, etc.).

[243] The N-oxides of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, the N-oxides can be prepared by treating the unoxidized form of a compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at about 0-80°C. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of the corresponding starting material.

[244] Compounds of formula (I) in non-oxidized form can be obtained from N-oxides of compounds of formula (I) by, for example, treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0-80°C.

[245] Protected derivatives of the compounds of formula (I) can be prepared by methods known to those of ordinary skill in the art. A detailed description of procedures applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[246] The symbols and conventions used in these processes, schemes, and examples herein are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard one- or three-letter abbreviations are generally used to denote amino acid residues that are assumed to be in the L-configuration, unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout this specification: g (grams); mg (milligrams); L (liters); ml (milliliters); µl (microliters); psi (pounds per square inch); M (molar); mM (millimolar); iv (intravenous); Hz (hertz); MHz (megahertz); mol (moles); mmol (millimoles); rt (room temperature); min. (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N-dimethylpropylene urea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et ₂ O (diethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm. (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (tert-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphine chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (metachloroperbenzoic acid).

[247] References to ether or _Et2O refer to diethyl ether; brine refers to saturated aqueous NaCl. Unless otherwise noted, all temperatures are in °C (degrees Celsius). All reactions were carried out under an inert atmosphere at room temperature unless otherwise noted.

[248] ¹ H NMR spectra were recorded on a Varian Mercury Plus 400 instrument. Chemical shifts are expressed in parts per million (ppm). Coupling constants are expressed in hertz (Hz). Splitting patterns describe the apparent multiplicity and are designated s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).

[249] Low-resolution mass spectra (MS) and compound purity data were obtained on a Shimadzu single quadrupole LC/MS system equipped with an electrospray ionization (ESI) source, a UV detector (220 and 254 nm), and an evaporative light scattering detector (ELSD). Thin layer chromatography was performed on Superchemgroup 0.25 mm silica gel plates (60F-254) visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or para-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co.,Ltd).

Synthesis schemes

[250] A compound of formula I or a pharmaceutically acceptable salt thereof can be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes can be readily devised by those skilled in the art in light of the present disclosure.

[251] In the reactions described hereinafter, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, if desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.

[252] Synthetic methods for preparing compounds according to the present invention are illustrated in the following schemes and examples. The starting materials are commercially available or can be prepared according to procedures known in the art or shown herein.

[253] The intermediate compounds shown in the following schemes are either known in the literature or can be prepared by a variety of methods known to those skilled in the art.

[254] One route to the synthesis of compounds of formula I of the present disclosure is shown in Scheme 1. Starting from intermediates II, which are either commercially available or known from the literature, intermediates of formula IV can be prepared by coupling compound II with intermediates of formula III. Further replacement of the leaving group in the intermediates of formula IV with an amine of formula V yielded compounds of formula I.

[255] As an illustration of the synthesis of compounds of formula I, one route to compounds of formula I1a is shown in Scheme 2. Starting from commercially available 5-bromo-7-azaindole IIa-A, compound IIa-C can be prepared by stepwise transformations involving replacement of the bromide with sodium methoxide and protection of NH with TTPSC1. Introduction of fluorine into compound IIa-C by directed ortho-metallation (DoM) afforded compound IIa-D. Cleavage of TIPS in compound IIa-D followed by bromination with NBS afforded bromides IIa, which can be further coupled with intermediate III using n-butyl lithium (n-BuLi) to afford compound IVa. Reaction of amine V with aryl fluoride IVa in the presence of a base such as N,N-diisopropylethylamine (DIPEA) afforded compound Ia.

[256] As a further illustration of the synthesis of compounds of formula I, one route to compounds of formula Ib is shown in Scheme 3. NH protection of azaindole IIb-A, which is commercially available, and fluorination with N-fluorobenzenesulfonimide afforded fluorides of formula IIb-C. Difluorides of formula IIb-D can be readily prepared from IIb-C using the DoM approach as shown in Scheme 2. TIPS cleavage in IIb-D followed by bromination with NBS converted IIb-D to bromides IIb-E, which can be converted to compound Ib by reactions as described in Scheme 3.

[257] In some cases, the order of the above reaction schemes may be changed to facilitate the reaction or to avoid undesirable reaction products. The following examples are provided to provide a more complete understanding of the present invention. Such examples are illustrative only and should not be construed as limiting the present invention in any way.

Intermediate connection A

[258] Methyl 2-chloro-4-phenoxybenzoate (A)

[259] Methyl 2-chloro-4-phenoxybenzoate (A) was prepared according to the procedure described in U.S. Patent No. 9,630,968, 2017, B1. Intermediate B

[260] 2-Chloro-6-fluoro-4-phenoxybenzaldehyde (B)

[261] Methyl 2-chloro-6-fluoro-4-phenoxybenzoate (B-1)

[262] A mixture of commercially available methyl 4-bromo-2-chloro-6-fluorobenzoate (1.04 g, 3.89 mmol), phenol (434 mg, 4.67 mmol), Pd(OAc) ₂ (90.0 mg, 0.401 mmol), Johnphos (1.7 mg, 0.0080 mmol) and K ₃ PO ₄ (1.7 g, 8.0 mmol) in toluene (30 mL) was stirred at 90 °C overnight under N ₂ . The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SC ₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with PE to give the title compound methyl 2-chloro-6-fluoro-4-phenoxybenzoate (B-1). MS ESI (m/z): 281 [M+1] ⁺ .

[263] (2-Chloro-6-fluoro-4-phenoxyphenyl)methanol (B-2)

[264] To a solution of methyl 2-chloro-6-fluoro-4-phenoxybenzoate (B-1) (50 mg, 0.18 mmol) in THF/EtOH (1 mL/0.5 mL) was added NaBH ₄ (20 mg, 0.53 mmol) and LiCl (22 mg, 0.53 mmol) in an ice bath. The resulting solution was stirred at rt for 2 h. Then the mixture was poured into ice water. The mixture was extracted with EtOAc, washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated to give crude (2-chloro-6-fluoro-4-phenoxyphenyl)methanol (B-2), which was used directly in the next step. ESIMS (m/z): 253 [M+1] ⁺ .

[265] 2-Chloro-6-fluoro-4-phenoxybenzaldehyde (B)

[266] A suspension of (2-chloro-6-fluoro-4-phenoxyphenyl)methanol (B-2) (780 mg, 3.08 mmol) and _MnO2 (2.0 g, 23 mmol) in toluene (15 mL) was stirred at 85 °C overnight under N2. The mixture was cooled to rt and filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (50:1) to give the title compound 2-chloro-6-fluoro-4-phenoxybenzaldehyde (B). ESI MS (m/z): 251 [M+1] ⁺ .

Example 1

[267] (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)sino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (1)

[268] 3-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1a)

[269] To a solution of commercially available 4-chloro-1H-pyrrolo[2,3-b]pyridine (1.525 g, 10.00 mmol) in DMF (15 mL) was added NBS (1.87 g, 10.50 mmol) at room temperature. The mixture was stirred at this temperature for 1.5 h. The mixture was poured into water (50 mL). The precipitated solid was collected by filtration and washed with water, air-dried to give 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1a). ESI MS (m/z): 231/233/235 (1:1.2:0.3) [M+1] ⁺ .

[270] (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone (1b)

[271] To a solution of 3-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1a) (244 mg, 1.06 mmol) in THF (7 mL) at -78 °C was added n-butyl lithium (2.5 M in hexanes, 0.89 mL, 2.2 mmol). The mixture was stirred at this temperature for 1 h. Then a solution of methyl 2-chloro-4-phenoxybenzoate (A) in THF (2 mL) was added dropwise. The mixture was stirred at -78 °C for another h. At this temperature, 1 N HCl (3 mL) was slowly added. The mixture was then warmed to rt, diluted with water (10 mL) and extracted with EtoAc (2×). The extracts were washed with brine and dried over Na ₂ SO ₄ . The solvents were evaporated under reduced pressure. The residue was purified by column chromatography on SiO ₂ , eluting with 20-70% EtoAc in hexanes to give (4-chloro-177-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone (1b). ESI MS (m/z): 383 [M+1] ⁺ .

[272] ((1r,4r)-4-Aminocyclohexyl)methanol trifluoroacetate (1c)

[273] To a solution of commercially available tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (1.00 g, 4.36 mmol) in DCE (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 h. The solvents were evaporated to give ((1r,4r)-4-aminocyclohexyl)methanol trifluoroacetate (1c). ESI MS (m/z): 130 [M+1] ⁺ .

[274] (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)- 1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (1)

[275] To a solution of ((1r,4r)-4-aminocyclohexyl)methanol trifluoroacetate (1c) (56.0 mg, 0.23 mmol) and (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone (1b) (44.0 mg, 0.115 mmol) in dioxane (1.5 mL) were added Pd ₂ (dba) ₃ (10.5 mg, 0.0115 mmol), xantphos (13.3 mg, 0.023 mmol) and CS ₂ CO ₃ (150 mg, 0.46 mmol). The mixture was heated under N2 at 110 °C for 54 h. After cooling, the mixture was diluted with water and extracted with EtOAc (2X). The extracts were dried over ^Na2SC4 and concentrated to give the crude product. This product was purified by silica gel chromatography eluting with 5% methanol in DCM to give (2-chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (1). ESI MS (m/z): 476 [M+1] ⁺ .

Example 2

[276] (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (2)

[277] ((2S,55R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (2a)

[278] The said compound ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (2a) was prepared according to the method described in US Patent Document No. 2018/051235.

[279] (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-2H-pyrrolo[2,3-b]pyridin-3-yl)methanone (2)

[280] To a solution of ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (2a) (122 mg, 0.50 mmol) and (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone (1b) (89.6 mg, 0.234 mmol) in n-butanol (2 mL) was added DIPEA (130 mg, 1.0 mmol). The mixture was heated under N ₂ at 125 °C overnight. After cooling, the mixture was diluted with water, extracted with EtoAc (3×). The extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. This product was purified by silica gel chromatography eluting with (DCM/MeOH=20:1) to give the title compound (2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-277-pyran-3-yl)amino)-177-pyrrolo[2,3-b]pyridin-3-yl)methanone (2). ESI MS (m/z): 478 [M+1] ⁺ .

Example 3

[281] (2-Chloro-6-fluoro-4-phenoxyphenyl)(4-(((3R, 6S)-6-(hydrooxymethyl)tetuahydro-2H-pyuan-3-yl)amino)-1H-pyrrolo[2,3-b]pyuidin-3-yl)methanone (3)

[282] (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol (3a)

[283] The title compound (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol (3a) was prepared according to the method for the synthesis of compound 1b by replacing methyl 2-chloro-4-phenoxybenzoate (A) with 2-chloro-6-fluoro-4-phenoxybenzaldehyde (B). ESI MS (m/z): 403 [M+1] ⁺ .

[284] (4-chloro-1H-pyruolo[2,3-b]pyuidin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanone (3b)

[285] To a solution of (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanol (3a) (30 mg, 0.07 mmol) in DMSO was added IBX (40 mg, 0.14 mmol) at rt. The resulting solution was stirred at rt for 1 h. The mixture was poured into ice water and extracted with EtOAc (3×). The extracts were washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. This product was purified by silica gel chromatography, eluting (PE/EA=3:1) to give the title compound (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanone (3b)._ESI MS (m/z): 401 [M+1] ⁺ .

[286] (2-Chloro-6-fluoro-4-phenoxyphenyl)(4-(((3R, 6S)-6-(hydrooxymethyl)tetuadiduo-2H-pyran-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (3)

[287] The title compound (2-chloro-6-fluoro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (3) was prepared according to the method for the synthesis of compound 2 by replacing (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxyphenyl)methanone (1b) with (4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-6-fluoro-4-phenoxyphenyl)methanone (3b). ESI MS (m/z): 496 [M+1] ⁺ .

[288] Based on essentially the same procedures described for Examples 1-3, the compounds of Examples 4-198, outlined in Table 1, were prepared from the corresponding starting materials, which are commercially available or known in the literature. The structures and names of the compounds of Examples 4-198 are presented in Table 1.

Kinase assay

[289] BTK(C481S) kinase activity was assayed at Reaction Biology Corporation. The BTK(C481S) reaction substrate, pEY (poly[Glu:Tyr] (4:1)) (Sigma, Cat#P7244-250MG), was prepared fresh in reaction buffer (20 mM Hepes (pH 7.5), 10 mM _MgCl2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM _{Na3VO4 ,} 2 mM DTT, 1% DMSO). BTK(C481S) (SignalChem, Cat#B10-12CH) was added to the substrate solution and mixed gently. The final concentrations of BTK (C481S) and substrate in the reaction mixture were 6 nM and 0.2 mg/mL, respectively. Compounds were tested in a 10-point concentration/response mode with 3-fold serial dilution steps starting from 1 μM.

[290] Compounds in 100% DMSO were added to the kinase reaction mixture using acoustic liquid delivery technology (Echo550; nanoliter range) and incubated for 20 min at room temperature. 10 μM [ ^33P ]-ATP (ATP: Sigma, Cat#: A7699; [ ^33P ]-ATP: Hartmann Analytic, Cat#: SCF-301-12) was added to the reaction mixture to initiate the reaction. The mixture was incubated for 120 min at room temperature. Radioactivity was determined using a proprietary filter binding assay. Kinase activity data were expressed as the percentage of residual kinase activity in test samples compared to vehicle (DMSO) reactions. _IC50 values were generated using GraphPad Prism software.

[291] Selected compounds obtained as described above were analyzed according to the biological procedures described in this document. The results are presented in Table 2.

Cell proliferation assays

[292] To examine whether the compound could inhibit BTK activity in cells, a mechanism-based assay was used using the DOHH2 cell (DSMZ catalog no. ACC47). In this assay, BTK inhibition was detected by inhibition of DOHH2 cell proliferation. Cells were harvested and seeded into 96-well plates at an optimized cell density (5000 cells/well). The plates were incubated at 37°C with 5% _CO2 for 4 h. Compounds were serially diluted and added to the plates at final concentrations of 10,000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, and 1.5 nM. The plates were incubated at 37°C with 5% _CO2 for 120 h. A 20 µl aliquot of the MTS/100 µl medium mixture was added to each well and the plates were incubated for exactly 2 h. The reaction was stopped by adding 25 µl of 10% SDS to each well. Absorbance was measured using a microplate reader at 490 nm and 650 nm (reference wavelength). _IC50 was calculated using GraphPad Prism 5.0.

[293] Selected compounds obtained as described above were analyzed according to the biological procedures described in this document. The results are presented in Table 3.

Pharmacokinetic analyses

[294] The objective of this study was to determine the pharmacokinetics of Example 71 and Example 75 in male Sprague-Dawley rats (supplied by Beijing Vital River Laboratory Animal Technology Co., Ltd.).

[295] Animals in Group 1 were administered the compound of Example 71 by a single intravenous bolus injection at a dose of 1 mg/kg, which was formulated in 60% Phosal 50 PG (lipoid, lot #368315-3180028/009): 30% PEG400 (Sigma, lot #MKCH6281): 10% ethanol (Merck, lot #K48244883634) at a concentration of 1 mg/mL as a solution. Animals in Group 2 were administered the compound of Example 71 by a single oral administration (PO) at a dose of 5 mg/kg, which was formulated in 60% Phosal 50 PG (lipoid, lot #368315-3180028/009): 30% PEG400 (Sigma, lot #MKCH6281): 10% ethanol (Merck, lot #K48244883634) at a concentration of 1 mg/mL as a solution. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. Plasma concentrations of the compound of Example 71 were determined using LC/MS/MS (LC: Waters UPLC; MS: API4000). The results are presented in Table 4.

[296] Animals in Group 3 were administered the compound of Example 75 by a single intravenous bolus injection at a dose of 2 mg/kg formulated in 10% DMSO (Sigma, Lot #LPC0S181): 60% PEG400 (Sigma, Lot #MKCH6281): 30% water at a concentration of 2 mg/mL as a solution. Animals in Group 4 were administered the compound of Example 75 by a single oral gavage (PO) at a dose of 10 mg/kg formulated in 10% DMSO (Sigma, Lot #LPC0S181): 60% PEG400 (Sigma, Lot #MKCH6281): 30% water at a concentration of 2 mg/mL as a solution. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. Plasma concentrations of Example 75 were determined using LC/MS/MS (LC: Waters UPLC; MS: Triple Quad 6500 plus). The results are presented in Table 4.

Claims (57)

1. Compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: where ring Q is chosen from , And , which are each unsubstituted or substituted by at least one substituent independently selected from R ^X ; L represents O; X ¹ , X ² , X ³ and X ⁴ are independently selected from CR ^X' and N, where no more than 1 of X ¹ , X ² , X ³ and X ⁴ can be N; R ¹ is C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X1 ; R ² is selected from hydrogen, halogen, CN, -OR ^A2 , -C(O)NR ^A2 R ^B2 and C _1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X2 ; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is selected from phenyl and heteroaryl, wherein phenyl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 ; each R ^A2 is independently selected from hydrogen, C _1-10 alkyl and C _3-10 cycloalkyl, wherein the alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X2 ; each R ^B2 represents hydrogen; each R ^X' is independently selected from hydrogen, deuterium, C _1-10 alkyl, C _3-10 cycloalkyl, halogen, CN and -(CR ^c1 R ^d1 ) _t OR ^b1 ; each R ^X is independently selected from hydrogen, C _1-10 alkyl, -(CR ^c1 R ^d1 ) _t OR ^b1 , (CR ^c1 R ^d1 ) _t NR ^a1 C(O)R ^bl , -(CR ^cl R ^dl ) _t NR ^a1 C(O)OR ^bl and -(CR ^cl R ^d1 ) _t NR ^al S(O) ₂ NR ^al R ^bl , wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^Y ; each R ^X1 is independently selected from hydrogen, halogen, CN, -(CR ^cl R ^dl ) _t OR ^bl , -(CR ^cl R ^dl ) _t NR ^a1 C(O)R ^bl , -(CR ^cl R ^dl ) _t NR ^al C(O)OR ^bl , -(CR ^cl R ^dl ) _t NR ^al C(O)NR ^al R ^bl , -(CR ^cl R ^dl ) _t N=S(O)R ^al R ^bl , -(CR ^cl R ^dl ) _t NR ^al S(O) _r R ^bl and -(CR ^cl R ^dl ) _t NR ^al S(O) ₂ NR ^al R ^bl ; R ^X2 represents deuterium; each R ^X5 is independently selected from hydrogen, halogen, CN, NO ₂ and -(CR ^cl R ^dl ) _t OR ^b1 ; each R ^al and each R ^bl is independently selected from hydrogen, C _1-10 alkyl and C _3-10 cycloalkyl; each R ^cl and each R ^dl represents hydrogen; each R ^Y is independently selected from -OR ^a2 , -(CR ^c2 R ^d2 ) _t OR ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 C(O)R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 CO ₂ R ^b2 , -(CR ^c2 R ^d2 ) _t NR ^a2 SO ₂ NR ^a2 R ^b2 , -NR ^a2 C(O)R ^b2 , -NR ^a2 C(O)OR ^b2 , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; each R ^a2 and each R ^b2 is independently selected from hydrogen and C _1-10 alkyl; each R ^c2 and each R ^d2 independently represent hydrogen; each r is independently chosen from 0, 1, and 2; each t is independently chosen from 0, 1, 2, 3, and 4; wherein heteroaryl is a 5- to 8-membered monocyclic aromatic ring containing one heteroatom selected from N, with the remaining ring atoms being carbon. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the R ^X substituent of ring Q is methyl, wherein the R ^Y substituent of methyl is OH. 3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-10 alkyl, wherein the alkyl is substituted with at least one substituent independently selected from R ^X1 . 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl, wherein the R ^X1 methyl substituent is selected from OH, CN, And 5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein the fragment formula (II) is selected from 6. A compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein the fragment formula (II) is selected from , . 7. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R ^X' is selected from hydrogen, F, Cl, Br, CN, methyl and methoxy. 8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R ^X' is selected from hydrogen, F, Cl and methyl. 9. A compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5 . 10. A compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from R ^X5 . 11. A compound according to any one of claims 1, 3, 9 and 10, or a pharmaceutically acceptable salt thereof, wherein “at least” means one, two, three or four 12. A compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein the substituent R ^X5 is selected from halogen and methoxy. 13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is pyridinyl and the pyridinyl is unsubstituted. 14. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenyl, 15. A compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen, F, Cl, methyl, ethyl, methoxy, ethoxy, -C(O)NH ₂ , CN, OH, And . 16. A compound selected from and its pharmaceutically acceptable salts. 17. A pharmaceutical composition that inhibits the kinase activity of BTK comprising a compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 18. The use of a compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the preparation of a medicament for the treatment, alleviation or prevention of a condition that is caused by inhibition of BTK. 19. Use of a compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 in the preparation of a medicament for the treatment of a cell proliferation disorder.