ITK inhibitors for increasing TH1 cell activity

Abstract

The present disclosure provides, inter alia, pharmaceutical compositions comprising IL-2 inducible T cell kinase (ITK) inhibitors, as well as methods for increasing Th1 cell activity, treating cancer, treating autoimmune diseases, treating allergies, and reversing T cell exhaustion by administering to a patient an effective amount of an IL-2 inducible T cell kinase (ITK) inhibitor.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Application No. 63 / 418,158, filed October 21, 2022, and U.S. Application No. 63 / 327,563, filed April 5, 2022, the disclosures of which are incorporated herein by reference in their entireties. [Background technology]

[0002] Interleukin 2-inducible T cell kinase (ITK) is a TEC family non-receptor tyrosine kinase expressed in T cells that plays a critical role in T cell receptor (TCR) signaling. TCR signaling regulates T cell development within the thymus, and the strength or duration of downstream signaling pathways determines thymocyte survival, maturation, and differentiation into mature T cells. ITK- / - mice exhibit defects in T helper 2 (Th2) differentiation while retaining the ability to differentiate into T helper 1 (Th1) cells and secrete IFNγ. Upon TCR stimulation, ITK is recruited to the membrane-bound SLP76 / LAT adaptor complex, where it is phosphorylated and activated by the src family kinase LCK. Activated ITK then phosphorylates PLCγ1, leading to Ca2+ mobilization and activation of growth and survival pathways, including MAPK and NFκB. Another TEC family kinase, known as resting lymphocyte kinase (RLK / TXK), is also expressed in T cells, is similarly activated by TCR-driven phosphorylation by src family kinases, and interacts with many of the same signaling components as ITK. - / - CD4+ T cells are impaired in T cell activation and differentiation, but not in ITK. - / - RLK - / -Double knockout T cells have a more substantial exacerbation of signaling defects and a profound loss of normal T cell function in mice. Therefore, selective inhibition of ITK while sparing RLK may be necessary to therapeutically modulate Th responses without affecting overall T-dependent immunity. Transgenic mice expressing kinase-dead ITK alleles were protected from inflammatory symptoms when challenged with ovalbumin, supporting ITK kinase inhibition as a strategy for T cell-driven inflammation. There is a need in the art for treatments of diseases regulated by Th responses. The present disclosure is directed to this, as well as other, important objectives. Summary of the Invention

[0003] Provided herein are methods for treating a patient with deficient Th1 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In some embodiments, the effective amount of the ITK inhibitor to increase Th1 activity is a dose of an ITK inhibitor to increase Th1 activity. + Increases the number of T cells, Th2 + Th1 vs. T cells + Increases the ratio of T cells to IL-4 + CD4 + IFNγ on T cells + CD4 + The effective amount of an ITK inhibitor for increasing Th1 activity is about 0.6 millimoles to about 1.6 millimoles of an ITK inhibitor per day. In some embodiments, the ITK inhibitor has selectivity for ITK that is at least 50-fold greater than its selectivity for resting lymphocyte kinase. In some embodiments, the ITK inhibitor is CPI-818.

[0004] Provided herein are methods for treating cancer, autoimmune diseases, or allergies in a patient in need thereof by administering to the patient about 0.6 millimoles per day to about 1.6 millimoles per day of an ITK inhibitor. In some embodiments, the ITK inhibitor has selectivity for ITK that is at least 50-fold greater than its selectivity for resting lymphocyte kinase. In some embodiments, the ITK inhibitor is CPI-818.

[0005] Provided herein are methods for treating cancer, autoimmune disease, or allergies in a patient in need thereof by administering CPI-818 to the patient in an amount of about 250 mg to about 1,000 mg per day. In some embodiments, a biological sample obtained from the patient has, relative to a control, (i) increased levels of LAG3, (ii) increased levels of TIGIT, (iii) increased levels of PD-1, (iv) decreased levels of IFNγ, (v) decreased levels of granzyme B, or (vi) a combination of two or more of the foregoing.

[0006] Provided herein are methods for reversing T cell exhaustion in a patient by administering to the patient an effective amount of an ITK inhibitor. In some embodiments, the ITK inhibitor has selectivity for ITK that is at least 50-fold greater than its selectivity for resting lymphocyte kinase. In some embodiments, the ITK inhibitor is CPI-818. In some embodiments, a patient is identified as having T cell exhaustion when a biological sample obtained from the patient has, compared to a control, (i) increased LAG3 levels, (ii) increased TIGIT levels, (iii) increased PD-1 levels, (iv) decreased IFNγ levels, (v) decreased granzyme B levels, or (vi) a combination of two or more of the foregoing.

[0007] These and other embodiments of the present disclosure are provided in greater detail herein. [Brief explanation of the drawings]

[0008] [Figure 1A]The structures and activities of ITK inhibitors are shown. Figures 1A-1B show the chemical structures of ITK inhibitors, and Figure 1C is a table showing the biochemical and functional inhibition of ITK activity. IC50 values ​​are the average of at least two technical replicates. Biochemical IC50 data were obtained by microfluidic assay. All other values ​​were obtained using the Lanthascreen format. [Figure 1B] The structures and activities of ITK inhibitors are shown. Figures 1A-1B show the chemical structures of ITK inhibitors, and Figure 1C is a table showing the biochemical and functional inhibition of ITK activity. IC50 values ​​are the average of at least two technical replicates. Biochemical IC50 data were obtained by microfluidic assay. All other values ​​were obtained using the Lanthascreen format. [Figure 1C] The structures and activities of ITK inhibitors are shown. Figures 1A-1B show the chemical structures of ITK inhibitors, and Figure 1C is a table showing the biochemical and functional inhibition of ITK activity. IC50 values ​​are the average of at least two technical replicates. Biochemical IC50 data were obtained by microfluidic assay. All other values ​​were obtained using the Lanthascreen format. [Figure 2A] Covalent irreversible inhibition of ITK by CPI-818. Figure 2A: Time-dependent inhibition of ITK by CPI-818. Thirteen concentrations of CPI-818 ranging from 10 μM to 2.4 nM were assayed. The curve is a best-fit solution to equation 3. [Figure 2B] Covalent irreversible inhibition of ITK by CPI-818 is shown in Figure 2B. A quadratic plot of kBs versus inhibitor concentration yields a hyperbolic curve, typical of enzyme inactivators with a mechanism according to Scheme 1 in Figure 11. The curve is a best-fit solution to equation 4, which gave kBs / Ki = 1.37 × 10 µM s for CPI-818 inactivation of ITK, and is the average of three independent determinations. [Figure 2C]Figure 2C shows covalent, irreversible inhibition of ITK by CPI-818. Dilution of BMS-509744 or CP-818-inhibited ITK mixtures into competitive probe solutions demonstrated reversible (T = 2.6 min) and irreversible inhibition, respectively. The curves are best-fit solutions to Equation 3. [Figure 2D] Figure 2D shows covalent irreversible inhibition of ITK by CPI-818. ITK enzyme activity remained inhibited even after addition of CPI-818-inhibited ITK to the substrate solution after extensive dialysis. [Figure 2E] Figure 2E shows covalent, irreversible inhibition of ITK by CPI-818. Removal of the Michael acceptor in the Cys442Ala ITK mutant significantly reduced its susceptibility to inhibition by CPI-818 compared to the wild-type enzyme. The curves were best-fit solutions to equation 2, yielding IC50 values ​​of 520 nM and 2.6 nM for the Cys442Ala and WT enzymes, respectively. [Figure 3] 1 is a table showing unique nested chymotryptic peptide sequences present in CPI-818 treated ITK, identified by deconvolution of the mass spectrum demonstrating an increased mass equivalent to the mass of CPI-818. [Figure 4] Chemical stability of CPI-818 acrylamide is shown. The acrylamide in CPI-818 is stable at 37°C in the presence of physiological glutathione concentrations, with minimal loss over 3 hours, similar to that of the approved drug ibrutinib. Each value is the result of a single replicate. [Figure 5A] Figure 5A shows that CPI-818 inhibits TCR signaling downstream of ITK and blocks IL-2 production. Jurkat T cells were stimulated with anti-CD3 for 30 seconds in the presence of increasing concentrations of CPI-818. Cell lysates were analyzed by immunoblotting using specific antibodies against total and phosphorylated PLCγ1 and ZAP-70. [Figure 5B]Figures 5B-5D show that CPI-818 inhibits TCR signaling downstream of ITK and blocks IL-2 production. Figures 5B-5D: CPI-818 inhibition of ERK and S6 phosphorylation and IL-2 secretion. ERK and S6 phosphorylation were measured by flow cytometry after CD3 / 28 crosslinking in human PBMCs. IC50 values ​​of 39 nM and 96 nM were obtained for ERK and S6, respectively; each data point is the average of three donors. Jurkat T cells were incubated with CPI-818, washed to remove the inhibitor, and stimulated with anti-CD3 for 18 hours. IL-2 was measured by AlphaLISA. A representative curve from one experiment is shown, along with the average of technical duplicates. An average IC50 of 136 nM was obtained from 15 independent determinations. The curve is a best-fit solution to equation 6. [Figure 5C] Figures 5B-5D show that CPI-818 inhibits TCR signaling downstream of ITK and blocks IL-2 production. Figures 5B-5D: CPI-818 inhibition of ERK and S6 phosphorylation and IL-2 secretion. ERK and S6 phosphorylation were measured by flow cytometry after CD3 / 28 crosslinking in human PBMCs. IC50 values ​​of 39 nM and 96 nM were obtained for ERK and S6, respectively; each data point is the average of three donors. Jurkat T cells were incubated with CPI-818, washed to remove the inhibitor, and stimulated with anti-CD3 for 18 hours. IL-2 was measured by AlphaLISA. A representative curve from one experiment is shown, along with the average of technical duplicates. An average IC50 of 136 nM was obtained from 15 independent determinations. The curve is a best-fit solution to equation 6. [Figure 5D]Figures 5B-5D show that CPI-818 inhibits TCR signaling downstream of ITK and blocks IL-2 production. Figures 5B-5D: CPI-818 inhibition of ERK and S6 phosphorylation and IL-2 secretion. ERK and S6 phosphorylation were measured by flow cytometry after CD3 / 28 crosslinking in human PBMCs. IC50 values ​​of 39 nM and 96 nM were obtained for ERK and S6, respectively; each data point is the average of three donors. Jurkat T cells were incubated with CPI-818, washed to remove the inhibitor, and stimulated with anti-CD3 for 18 hours. IL-2 was measured by AlphaLISA. A representative curve from one experiment is shown, along with the average of technical duplicates. An average IC50 of 136 nM was obtained from 15 independent determinations. The curve is a best-fit solution to equation 6. [Figure 6A] Figure 6 shows the turnover of ITK in Jurkat and primary human T cells. Data from a representative experiment for ITK degradation and synthesis are shown; each data point is the average of technical duplicates in Jurkat cells (Figure 6A) and primary human T cells (Figure 6B). The half-lives for degradation and synthesis ranged from 6.9 h to 8.2 h for both Jurkat and primary human T cells. The curves are best-fit solutions to single-exponential equations for decay and association. [Figure 6B] Figure 6 shows the turnover of ITK in Jurkat and primary human T cells. Data from a representative experiment for ITK degradation and synthesis are shown; each data point is the average of technical duplicates in Jurkat cells (Figure 6A) and primary human T cells (Figure 6B). The half-lives for degradation and synthesis ranged from 6.9 h to 8.2 h for both Jurkat and primary human T cells. The curves are best-fit solutions to single-exponential equations for decay and association. [Figure 7] Figure 1 shows in vivo ITK occupancy in mice. CPI-818 potently and persistently inhibited mouse splenocyte ITK after a single 50 mg / kg PO dose, resulting in very high levels of enzyme occupancy. Data points are the average of four (PK) and six (occupancy) animals. [Figure 8A]Selective ITK inhibition by CPI-818 biases naive human T cells toward a Th-1 phenotype. Figure 8A: CPI-818 (1 μM) induced Th1 bias and a two-fold increase in the ratio of IFNγ+ CD4+ T cells to IL4+ CD4+ T cells in 12 normal donors. [Figure 8B] Selective ITK inhibition by CPI-818 biases naive human T cells toward a Th-1 phenotype. (Figure 8B) CPI-818 (≥1 μM) reduced total cell numbers while maintaining cell viability. [Figure 9A] Selective inhibition of ITK preserved NK-mediated ADCC. Figure 9A: Lymphocyte subsets (5 donors / cell type) were purified from peripheral blood of 22 healthy donors. Expression of ITK and RLK relative to the housekeeping gene IPO8 was determined by qPCR. [Figure 9B] Selective inhibition of ITK preserved NK-mediated ADCC. Figure 9B: Peripheral blood NK cells from seven healthy donors were cocultured with anti-CD20-conjugated target cells (B cell lymphoma line Jeko) and inhibitors at a 10:1 ratio for 18 hours. Cell lysis was detected by viability dye using flow cytometry. The percentage of killed target cells in DMSO-treated samples was set as maximum lysis (100%). CPI-818 (ITK-specific), CP-1392 (RLK-specific), and CP-2193 (ITK / RLK dual inhibitor) are covalent small molecule Tec kinase inhibitors. [Figure 10A]Figure 10 shows the efficacy of CPI-818 treatment in a mouse model of colitis. CB-17 SCID mice (10 mice / group) were fed a control diet or a CPI-818-infused diet (300 mg / kg / day) with or without anti-IL-12 / 23 treatment one week before receiving CD4+CD45RBhi T cells from BALB / c mice. Body weight (Figure 10A) was monitored during the survival phase. Mice were sacrificed on day 48, and colon weight (Figure 10B) and length (Figure 10C) were recorded. The distal portion of each colon was fixed and subjected to histological analysis. Infiltrating CD3+ T cells were counted (Figure 10D), and histological lesions were scored (Figure 10E). *Differences between the control and CPI-818-treated groups for each of the four lesion categories were statistically significant (from left to right: P=0.004, P<0.002, P<0.008, and P=0.037). [Figure 10B] Figure 10 shows the efficacy of CPI-818 treatment in a mouse model of colitis. CB-17 SCID mice (10 mice / group) were fed a control diet or a CPI-818-infused diet (300 mg / kg / day) with or without anti-IL-12 / 23 treatment one week before receiving CD4+CD45RBhi T cells from BALB / c mice. Body weight (Figure 10A) was monitored during the survival phase. Mice were sacrificed on day 48, and colon weight (Figure 10B) and length (Figure 10C) were recorded. The distal portion of each colon was fixed and subjected to histological analysis. Infiltrating CD3+ T cells were counted (Figure 10D), and histological lesions were scored (Figure 10E). *Differences between the control and CPI-818-treated groups for each of the four lesion categories were statistically significant (from left to right: P=0.004, P<0.002, P<0.008, and P=0.037). [Figure 10C]Figure 10 shows the efficacy of CPI-818 treatment in a mouse model of colitis. CB-17 SCID mice (10 mice / group) were fed a control diet or a CPI-818-infused diet (300 mg / kg / day) with or without anti-IL-12 / 23 treatment one week before receiving CD4+CD45RBhi T cells from BALB / c mice. Body weight (Figure 10A) was monitored during the survival phase. Mice were sacrificed on day 48, and colon weight (Figure 10B) and length (Figure 10C) were recorded. The distal portion of each colon was fixed and subjected to histological analysis. Infiltrating CD3+ T cells were counted (Figure 10D), and histological lesions were scored (Figure 10E). *Differences between the control and CPI-818-treated groups for each of the four lesion categories were statistically significant (from left to right: P=0.004, P<0.002, P<0.008, and P=0.037). [Figure 10D] Figure 10 shows the efficacy of CPI-818 treatment in a mouse model of colitis. CB-17 SCID mice (10 mice / group) were fed a control diet or a CPI-818-infused diet (300 mg / kg / day) with or without anti-IL-12 / 23 treatment one week before receiving CD4+CD45RBhi T cells from BALB / c mice. Body weight (Figure 10A) was monitored during the survival phase. Mice were sacrificed on day 48, and colon weight (Figure 10B) and length (Figure 10C) were recorded. The distal portion of each colon was fixed and subjected to histological analysis. Infiltrating CD3+ T cells were counted (Figure 10D), and histological lesions were scored (Figure 10E). *Differences between the control and CPI-818-treated groups for each of the four lesion categories were statistically significant (from left to right: P=0.004, P<0.002, P<0.008, and P=0.037). [Figure 10E]Figure 10 shows the efficacy of CPI-818 treatment in a mouse model of colitis. CB-17 SCID mice (10 mice / group) were fed a control diet or a CPI-818-infused diet (300 mg / kg / day) with or without anti-IL-12 / 23 treatment one week before receiving CD4+CD45RBhi T cells from BALB / c mice. Body weight (Figure 10A) was monitored during the survival phase. Mice were sacrificed on day 48, and colon weight (Figure 10B) and length (Figure 10C) were recorded. The distal portion of each colon was fixed and subjected to histological analysis. Infiltrating CD3+ T cells were counted (Figure 10D), and histological lesions were scored (Figure 10E). *Differences between the control and CPI-818-treated groups for each of the four lesion categories were statistically significant (from left to right: P=0.004, P<0.002, P<0.008, and P=0.037). [Figure 11] 1 is a scheme showing the time-dependent irreversible inhibition of ITK. [Figure 12] This table shows the selectivity of CPI-818 for ITK among 11 kinases in the human kinome that contain a conserved cysteine ​​at a position homologous to Cys-442 in ITK. Selectivity in a functional autophosphorylation assay was measured for five TEC family kinases and JAK3. Values ​​are the average of technical duplicates for both assays. [Figure 13] RLK-selective and ITK / RLK dual-selective inhibitors CP 1392 and CP-2193 are shown. [Figure 14A] ITK active site occupancy is shown. Figure 14A: Occupancy was measured in Jurkat cells after treatment with CP-464 (37°C, 1 hour). Each point is the average of technical duplicates. [Figure 14B] ITK active site occupancy is shown. Figure 14B: Chemical structure of biotinylated probe CP-613. [Figure 15A] Figure 15 shows the PK / PD relationship of CPI-818 in dogs (QD dose) and mice (BID dose and chow formulation). Figure 15A: Plasma CPI-818 and ITK occupancy in PBMCs was measured in dogs after a single 5 mg / kg PO dose. Each data point is the mean from three animals. [Figure 15B] Figure 15B shows the PK / PD relationship of CPI-818 in dogs (QD dose) and mice (BID dose and chow formulation). Figure 15B: Plasma CPI-818 and splenocyte ITK occupancy were measured in mice after 50 mg / kg BID, PO administration. Each data point is the mean from 3 (PK) and 4 (occupancy) animals. [Figure 15C] Figure 15C shows the PK / PD relationship of CPI-818 in dogs (QD dose) and mice (BID dose and chow formulation). Figure 15C: Plasma CPI-818 and splenocyte ITK occupancy were measured in mice after administration of a chow formulated to deliver 300 mg / kg / day. Each data point is the average from five animals for PK and occupancy measurements. [Figure 16A] The effect of 1 μM CPI-818 on IFNγ (FIG. 16A) and IL-4 (FIG. 16B) production by human CD4+ T cells is shown. [Figure 16B] The effect of 1 μM CPI-818 on IFNγ (FIG. 16A) and IL-4 (FIG. 16B) production by human CD4+ T cells is shown. [Figure 17A] H&E stained mouse proximal colons are shown in naive animals (FIG. 17A), untreated disease control animals showing histological features of colitis (FIG. 17B), and animals treated daily with CPI-818 (FIG. 17C), where normal tissue architecture and composition was preserved. Scale bar = 400 μm. Prevention of inflammatory bowel disease can be seen by histology and reduced colon weight (FIG. 17D). Positive control = anti-IL12 / 23. [Figure 17B] H&E stained mouse proximal colons are shown in naive animals (FIG. 17A), untreated disease control animals showing histological features of colitis (FIG. 17B), and animals treated daily with CPI-818 (FIG. 17C), where normal tissue architecture and composition was preserved. Scale bar = 400 μm. Prevention of inflammatory bowel disease can be seen by histology and reduced colon weight (FIG. 17D). Positive control = anti-IL12 / 23. [Figure 17C]H&E stained mouse proximal colons are shown in naive animals (FIG. 17A), untreated disease control animals showing histological features of colitis (FIG. 17B), and animals treated daily with CPI-818 (FIG. 17C), where normal tissue architecture and composition was preserved. Scale bar = 400 μm. Prevention of inflammatory bowel disease can be seen by histology and reduced colon weight (FIG. 17D). Positive control = anti-IL12 / 23. [Figure 17D] H&E stained mouse proximal colons are shown in naive animals (FIG. 17A), untreated disease control animals showing histological features of colitis (FIG. 17B), and animals treated daily with CPI-818 (FIG. 17C), where normal tissue architecture and composition was preserved. Scale bar = 400 μm. Prevention of inflammatory bowel disease can be seen by histology and reduced colon weight (FIG. 17D). Positive control = anti-IL12 / 23. [Figure 18] 1 shows the antiproliferative effect of CPI-818 in the peripheral blood of three human patients with cutaneous T-cell lymphoma and circulating malignant Sézary cells and a healthy donor. Referring to the graph, the top line is normal CD8 cells, the middle line is normal CD4 cells, and the bottom line is Sézary cells. [Figure 19] 1 is a table showing the in vivo plasma concentrations of CPI-818 when administered at four different doses to human patients with peripheral T-cell lymphoma. In each case, the doses (100 mg, 200 mg, 400 mg, 600 mg) were administered twice daily to the human patients. [Figure 20] It is shown that the best responders received a dose of 200 mg BID and that the response to treatment was not a linear dose-response curve. [Figure 21A] Steady-state peak (FIG. 21A) and steady-state trough (FIG. 21B) ITK occupancy for CPI-818 are shown. Peak occupancy was consistently high, with average values ​​of at least 90%. Trough occupancy was dose-dependent, approximately 90% at the 400 mg BID and 600 mg BID doses, but varied by subject. [Figure 21B]Steady-state peak (FIG. 21A) and steady-state trough (FIG. 21B) ITK occupancy for CPI-818 are shown. Peak occupancy was consistently high, with average values ​​of at least 90%. Trough occupancy was dose-dependent, approximately 90% at the 400 mg BID and 600 mg BID doses, but varied by subject. [Figure 22A] Figure 22A shows the antitumor activity of CPI-818 evaluated in human clinical trials. Figure 22A shows the antitumor activity of four doses of CPI-818 evaluated in human clinical trials (100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID). [Figure 22B] Figure 22B shows the antitumor activity of CPI-818 evaluated in a human clinical trial. Figure 22B shows the antitumor activity of CPI-818 at a dose of 200 mg BID evaluated in a human clinical trial. Each lane represents a patient, and the length indicates the treatment time. The treatment cycle is 21 days, and the cycle is then repeated until the patient experiences tumor progression or unacceptable toxicity. The best response occurred at a dose of 200 mg BID. [Figure 23] This figure shows the treatment results of a patient with peripheral T cell lymphoma not otherwise specified (PTCL-NOS). The patient had stable disease over seven cycles (i.e., C1D1, C4D1, C7D1, each 21-day cycle), discontinued treatment for three weeks (DH or drug holiday), and then resumed treatment for 10 cycles. The patient achieved a complete response in treatment cycle 17 after one year of treatment. The duration of the complete response was 19 months. PET is the Deauville PET score; ND is not performed; SD is stable disease; and CR is complete response. [Figure 24]Results are shown for a patient with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), treated with CPI-818 after 8 and 15 days. The patient demonstrated dramatic reduction in subcutaneous (SQ) tumors and improvement in platelet (PLT) and lactate dehydrogenase (LDH) levels within 8 to 15 days of initiating treatment. Significantly elevated eosinophil counts decreased during therapy. [Figure 25A] These results show that CPI-818 induces Th1 bias and reduces eosinophils. CPI-818 increased Th1 cells and simultaneously reduced tumor responses and Th17 pro-inflammatory cells (Figure 25A), resulting in a significant reduction in hypereosinophilia (Figure 25B). These findings are consistent with the inhibitory effects of CPI-818 on tumor and / or normal Th2 cells. [Figure 25B] These results show that CPI-818 induces Th1 bias and reduces eosinophils. CPI-818 increased Th1 cells and simultaneously reduced tumor responses and Th17 pro-inflammatory cells (Figure 25A), resulting in a significant reduction in hypereosinophilia (Figure 25B). These findings are consistent with the inhibitory effects of CPI-818 on tumor and / or normal Th2 cells. [Figure 26A] Figure 26A shows that CPI-818 treatment increases Th1 cells (Figure 26A) and CD4+ effector cells (Figure 26B) in the blood and tumors of patients with peripheral T-cell lymphoma. In Figure 26A, the upper dots represent Th1 cells in the tumor, and the lower dots represent Th1 cells in the blood on day 84. In Figure 26B, the upper dots represent CD4+ effector cells in the blood, and the lower dots represent CD4+ effector cells in the tumor on day 84. CPI-818 treatment consisted of oral administration of 200 mg of CPI-818 twice daily (BID). [Figure 26B]Figure 26A shows that CPI-818 treatment increases Th1 cells (Figure 26A) and CD4+ effector cells (Figure 26B) in the blood and tumors of patients with peripheral T-cell lymphoma. In Figure 26A, the upper dots represent Th1 cells in the tumor, and the lower dots represent Th1 cells in the blood on day 84. In Figure 26B, the upper dots represent CD4+ effector cells in the blood, and the lower dots represent CD4+ effector cells in the tumor on day 84. CPI-818 treatment consisted of oral administration of 200 mg of CPI-818 twice daily (BID). [Figure 27] This study demonstrates the effect of CPI-818 treatment on Th1 / Th2 differentiation in a patient with peripheral T-cell lymphoma. Note that a 4-week treatment break was initiated at week 23. CPI-818 treatment consisted of 200 mg of CPI-818 administered orally twice daily (BID), excluding the 4-week break. The patient's skin lesions began to respond to treatment after resuming CPI-818 after the 4-week treatment break. [Figure 28A] We demonstrate that CPI-818 inhibits Th2 cytokine production in vitro. Figure 28A shows cytokine production in CD4+ cells from three normal subjects at various CPI-818 concentrations (μM). Figure 28B shows cytokine production in Sézary cells from two subjects at various CPI-818 concentrations (μM). Briefly, normal CD4+ cells and Sézary cells were stimulated with anti-CD3 / 28 / 2 in the presence of various concentrations of CPI-818, and cytokines secreted into the supernatant were measured by immunoassay. This finding indicates that CPI-818 blocks cytokines secreted by Th2 cells. This is important because cytokines secreted by Th2 cells are involved in inflammation, allergy, and autoimmunity. Interferon gamma (IFNg) is produced by Th1 cells and is inhibited only by high concentrations of CPI-818. High concentrations of CPI-818 cause general T cell inhibition of proliferation / function, whereas intermediate concentrations of CPI-818 affect differentiation. [Figure 28B]We demonstrate that CPI-818 inhibits Th2 cytokine production in vitro. Figure 28A shows cytokine production in CD4+ cells from three normal subjects at various CPI-818 concentrations (μM). Figure 28B shows cytokine production in Sézary cells from two subjects at various CPI-818 concentrations (μM). Briefly, normal CD4+ cells and Sézary cells were stimulated with anti-CD3 / 28 / 2 in the presence of various concentrations of CPI-818, and cytokines secreted into the supernatant were measured by immunoassay. This finding indicates that CPI-818 blocks cytokines secreted by Th2 cells. This is important because cytokines secreted by Th2 cells are involved in inflammation, allergy, and autoimmunity. Interferon gamma (IFNg) is produced by Th1 cells and is inhibited only by high concentrations of CPI-818. High concentrations of CPI-818 cause general T cell inhibition of proliferation / function, whereas intermediate concentrations of CPI-818 affect differentiation. [Figure 28C] CPI-818 inhibits Th2 cytokine production in vitro. In Figure 28C, human peripheral blood CD4+ T cells were stimulated with anti-CD3 / 28 / 2, and a dose-dependent inhibition of Th2 cytokines was observed. There was no effect on Th1-dependent IFNg except at high concentrations. Inhibition of Th2 cells blocks the production of various inflammatory cytokines, including IL-4, IL-5, IL-9, IL-13, and IL17a. [Figure 29A] CPI-818 inhibits lymphadenopathy (FIG. 29A) and proteinuria (FIG. 29B) in the murine MRL lymphoproliferative line (also known as MRL / lpr− / −) lupus model. [Figure 29B] CPI-818 inhibits lymphadenopathy (FIG. 29A) and proteinuria (FIG. 29B) in the murine MRL lymphoproliferative line (also known as MRL / lpr− / −) lupus model. [Figure 30] 1 shows that CPI-818 significantly reduced skin thickening and skin inflammation in an imiquimod-induced model of psoriasis. [Figure 31A]CPI-818 is effective in animal models of pulmonary fibrosis. Figures 31A-B show that CPI-818 reduced lung weight and BALF leukocytes in a bleomycin-induced mouse pulmonary fibrosis model. In Figure 31A, *p=0.003, **p=0.002, ***p=0.0001 compared to G2 placebo. [Figure 31B] CPI-818 is effective in animal models of pulmonary fibrosis. Figures 31A-B show that CPI-818 reduced lung weight and BALF leukocytes in a bleomycin-induced mouse pulmonary fibrosis model. *p=0.01 compared to G2 placebo in Figure 31B. [Figure 31C] Figure 31C shows that CPI-818 is effective in animal models of pulmonary fibrosis. Figure 31C shows that CPI-818 reduced Ashcroft scores comparable to (at 10 mg / kg) or better than (at 30 mg / kg) nintadenib (OFEV® by Boehringer Ingelheim Pharmaceuticals), an FDA-approved drug for the treatment of idiopathic pulmonary fibrosis. *p=0.004, **p=0.0008, ***p=0.005 compared to G2 placebo. [Figure 31D] Figure 31D shows the plasma concentrations of CPI-818 in mice at doses of 10 mg / mL and 30 mg / mL, demonstrating that CPI-818 is effective in an animal model of pulmonary fibrosis. [Figure 32] Figure 1 shows that various concentrations of CPI-818 downregulate biomarkers of T cell exhaustion (i.e., LAG3, TIGIT, and PD-1) in human CD4 T cells. [Figure 33A] Figure 33 shows that CPI-818 treatment reverses T cell exhaustion by increasing granzyme B (Figure 33A) and IFNγ (Figure 33B) levels. [Figure 33B] Figure 33 shows that CPI-818 treatment reverses T cell exhaustion by increasing granzyme B (Figure 33A) and IFNγ (Figure 33B) levels. DETAILED DESCRIPTION OF THE INVENTION

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of the present disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not intended to limit the scope of the present disclosure.

[0010] The terms "interleukin-2-inducible T cell kinase" and "ITK" refer to a protein (including homologs, isoforms, and functional fragments thereof) having interleukin-2-inducible T cell kinase activity. The terms include any recombinant or naturally occurring form of ITK or a variant thereof that maintains ITK activity (e.g., within the range of at least 60%, 70%, 80%, 90%, or 100% activity compared to wild-type ITK). In embodiments, the interleukin-2-inducible T cell kinase protein encoded by the ITK gene has an amino acid sequence set forth in or corresponding to Entrez 3702, UniProt Q08881, or RefSeq(protein) NP_005537. In embodiments, the ITK gene has a nucleic acid sequence set forth in RefSeq(mRNA) NM_005546. In embodiments, the sequence corresponds to GI:15718680, NP_005537.3, NM_005546.3, or GI:21614549.

[0011] The terms "Tec kinase" and "Tec kinase family" refer to a protein family of non-receptor protein tyrosine kinases (including homologs, isoforms, and functional fragments thereof) that includes the proteins TEC, BTK (Bruton's Tyrosine Kinase), ITK / EMT / TSK, BMX, and TXK / RLK. The terms include any recombinant or naturally occurring form of a Tec family kinase or variant thereof that maintains a Tec family kinase activity (e.g., within the range of at least 50%, 60%, 70%, 80%, 90%, or 100% activity compared to a wild-type Tec family kinase).

[0012] With respect to protein-inhibitor interactions, terms such as "inhibit," "inhibit," "inhibiting," and the like refer to negatively affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptom. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Thus, inhibition includes at least partially or completely blocking a stimulus, reducing, preventing, or delaying activation of a signal transduction or enzymatic activity or amount of a protein, or inactivating, desensitizing, or downregulating. In embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0013] The term "LAG3" or "lymphocyte-activation gene 3 protein" refers to a protein having LAG3 activity (including homologs, isoforms, and functional fragments thereof). This term includes any recombinant or naturally occurring form of LAG3 or a variant thereof that maintains LAG3 activity (e.g., within the range of at least 60%, 70%, 80%, 90%, or 100% activity compared to wild-type LAG3). In embodiments, the LAG3 protein has the amino acid sequence set forth in or corresponding to UniProt P18627. In embodiments, the LAG3 gene has the nucleic acid sequence set forth in NCBI Gene ID No. 3902.

[0014] The term "TIGIT" or "T cell immunoreceptor having an Ig domain and an ITIM domain" refers to a protein having TIGIT activity (including homologs, isoforms, and functional fragments thereof). This term includes any recombinant or naturally occurring form of TIGIT or a variant thereof that maintains TIGIT activity (e.g., within the range of at least 60%, 70%, 80%, 90%, or 100% activity compared to wild-type TIGIT). In embodiments, the TIGIT protein has the amino acid sequence set forth in or corresponding to UniProt Q495A1. In embodiments, the TIGIT gene has the nucleic acid sequence set forth in NCBI Gene ID No. 201633.

[0015] The term "PD-1" or "programmed cell death protein 1" refers to a protein having PD-1 activity (including homologs, isoforms, and functional fragments thereof). This term includes any recombinant or naturally occurring form of PD-1 or a variant thereof that maintains PD-1 activity (e.g., within the range of at least 60%, 70%, 80%, 90%, or 100% activity compared to wild-type TIGIT). In embodiments, the PD-1 protein encoded by the PDCD1 gene has the amino acid sequence set forth in or corresponding to UniProt Q15116. In embodiments, the PDCD1 gene has the nucleic acid sequence set forth in NCBI Gene ID No. 5133.

[0016] "CPI-818" refers to a compound of formula (A) or a pharmaceutically acceptable salt thereof. In embodiments, CPI-818 is in the form of a free base. CPI-818 and compounds of formula (A) have the following structure:

[0017] [ka] It has.

[0018] The abbreviations used herein have their conventional meanings within the chemical and biological arts. The chemical structures and formulae described herein are constructed according to the standard rules of chemical valency well known in the chemical arts. Substituent groups, when specified by their conventional chemical formulae written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CHO- is equivalent to -OCH-.

[0019] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monovalent, or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. An alkyl can contain the specified number of carbon atoms (e.g., C1-C6). 10means 1 to 10 carbons). An alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl, as well as homologs and isomers of groups such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those containing one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, and 3-butynyl, as well as higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. Alkenyl may contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds.Alkynyl may contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0020] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited to, by -CHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0021] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain containing at least one carbon atom and at least one heteroatom, or a combination thereof, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom may be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl groups are non-cyclizing chains. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2NH-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH-2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may contain one heteroatom. A heteroalkyl moiety may contain two, optionally different, heteroatoms. A heteroalkyl moiety may contain three, optionally different, heteroatoms. A heteroalkyl moiety may contain four, optionally different, heteroatoms. A heteroalkyl moiety can contain five, any different heteroatoms. A heteroalkyl moiety can contain up to eight, any different heteroatoms.

[0022] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R''.

[0023] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyls and heterocycloalkyls are not aromatic. Additionally, for heterocycloalkyls, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. In embodiments, a cycloalkyl is a spirocyclic cycloalkyl, and the spirocyclic ring is a cycloalkyl ring. In embodiments, a cycloalkyl is a fused-ring cycloalkyl, and the fused ring is a cycloalkyl ring. In embodiments, a cycloalkyl is a bridged-ring cycloalkyl, and the bridged ring is a cycloalkyl ring. In embodiments, a bridged-ring cycloalkyl is

[0024] [ka] Non-limiting examples of bridged ring heterocycloalkyl include:

[0025] [ka] In some embodiments, the cycloalkyl is monocyclic. In some embodiments, the cycloalkyl is 2 rings. In some embodiments, the cycloalkyl is 3 rings. In some embodiments, the cycloalkyl is 4 rings. In some embodiments, the cycloalkyl is 5 rings. In some embodiments, the cycloalkyl is polycyclic. In some embodiments, the heterocycloalkyl is a spirocyclic heterocycloalkyl, where the spirocyclic ring is one or more heterocycloalkyl rings and, optionally, one or more cycloalkyl rings. For example, a spirocyclic heterocycloalkyl is

[0026] [ka] In embodiments, the heterocycloalkyl is a fused-ring heterocycloalkyl, where the fused ring is one or more heterocycloalkyl rings and, optionally, one or more cycloalkyl rings. In embodiments, the fused-ring heterocycloalkyl is

[0027] [ka] In embodiments, the heterocycloalkyl is a bridged-ring heterocycloalkyl, where the bridged ring is one or more heterocycloalkyl rings and, optionally, one or more cycloalkyl rings. In embodiments, the ring of a spirocyclic, fused-ring, or bridged-ring heterocycloalkyl is a heterocyclic ring. In embodiments, the heterocycloalkyl is monocyclic. In embodiments, the heterocycloalkyl is two rings. In embodiments, the heterocycloalkyl is three rings. In embodiments, the heterocycloalkyl is four rings. In embodiments, the heterocycloalkyl is five rings. In embodiments, the heterocycloalkyl is polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0028] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0029] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0030] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having five members and the other having six members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring being a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring being a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom. In embodiments, the aryl is a fused ring aryl, where the fused ring is one or more aryl rings and, optionally, one or more cycloalkyl and / or heterocycloalkyl rings. In embodiments, the aryl is a bridged ring aryl, where the bridged ring is one or more aryl rings and, optionally, one or more cycloalkyl and / or heterocycloalkyl rings. In embodiments, the ring of the fused ring aryl or bridged ring aryl is an aryl ring. In embodiments, the aryl is monocyclic. In embodiments, the aryl is two rings. In embodiments, the aryl is a 3-ring group. In embodiments, the aryl is a 4-ring group. In embodiments, the aryl is a 5-ring group. In embodiments, the aryl is polycyclic.In embodiments, the heteroaryl is a fused-ring heteroaryl, wherein the fused ring is one or more heteroaryl rings and, optionally, one or more cycloalkyl, heterocycloalkyl, and / or aryl rings. In embodiments, the heteroaryl is a bridged-ring heteroaryl, wherein the bridged ring is one or more heteroaryl rings and, optionally, one or more cycloalkyl, heterocycloalkyl, and / or aryl rings. In embodiments, a ring of the fused-ring heteroaryl or bridged-ring heteroaryl is a heteroaryl ring. In embodiments, the heteroaryl is monocyclic. In embodiments, the heteroaryl is two rings. In embodiments, the heteroaryl is three rings. In embodiments, the heteroaryl is four rings. In embodiments, the heteroaryl is five rings. In embodiments, the heteroaryl is polycyclic. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0031] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring can be the same or different. The individual rings within a spirocyclic ring can be substituted or unsubstituted and can have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for each ring within a spirocyclic ring are the possible substituents for the same ring when not part of a spirocyclic ring (e.g., substituents for a cycloalkyl ring or heterocycloalkyl ring). The spirocyclic ring can be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group can be any of the rings in the list immediately above, including having all rings of one type (e.g., all rings are substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0032] symbol

[0033] [ka] and "-" indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0034] The term "oxo" means an oxygen that is double bonded to a carbon atom.

[0035] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (alkylene linker). In embodiments, the alkylarylene group has the formula:

[0036] [ka] It has.

[0037] The alkylarylene moiety can be optionally substituted (e.g., with a substituent group) at the alkylene portion or in the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH, -SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In some embodiments, the alkylarylene is unsubstituted.

[0038] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0039] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R' in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. NR'R'', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)R', -S(O)NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SOR'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected as each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0040] Similar to the substituents described for the alkyl radical, substituents on the aryl and heteroaryl groups vary and can include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′′, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′′′, —NR″C(O)R′, —NR-C(NR′R″R′′)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′NR′ and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected for each R', R", R'", and R"" group when more than one of these groups is present.

[0041] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be designated as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence); in the case of a fused, bridged, or spirocyclic ring, a substituent shown as attached to one member of the fused, bridged, or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on any of the fused, bridged, or spirocyclic rings (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused, bridged, or spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused, bridged, or spirocyclic ring, any atom of the fused, bridged, or spirocyclic ring, according to the rules of chemical valence. When a ring, fused, bridged, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused, bridged, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown in a structure or formula with a floating substituent as being attached to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), and the heteroatom is attached to the floating substituent, it will be understood that the substituent replaces the hydrogen according to the rules of chemical valence.

[0042] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure to form a bridged ring structure.

[0043] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0044] "Heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0045] As used herein, "substituent group" means a group selected from the following moieties: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2 unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 heterocycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B)(i) oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHC l2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 heterocycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NH OH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 heterocycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each substituted with at least one substituent selected from oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NH OH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 heterocycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from aryl, aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0046] As used herein, a "size-limited substituent" or "size-limited substituent group" refers to a group selected from all of the substituents described above for "substituent group," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0047] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0048] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. In some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent group. In some embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In some embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0049] In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl can be a substituted or unsubstituted 5-10 membered heteroaryl. In embodiments of the compounds herein, each substituted or unsubstituted alkylene can be a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0050] In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene.

[0051] Certain compounds may have asymmetric carbon atoms (optical or chiral centers) or double bonds, and the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids, are encompassed by the present invention. The compounds do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified. Unless otherwise specified, a structure depicted herein is also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Thus, single stereochemical isomers of a compound, as well as enantiomeric and diastereomeric mixtures, are within the scope of this disclosure. The term "isomer" refers to compounds that have the same number and type of atoms, and thus the same molecular weight, but differ in terms of the structural arrangement or configuration of the atoms. The term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. It will be apparent to those skilled in the art that certain compounds may exist in tautomeric forms, and all such tautomeric forms of the compound are within the scope of the disclosure.

[0052] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14Compounds having the present structures except for the replacement of a carbon by a C-enriched carbon are within the scope of this disclosure. The compounds may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 The compound may be radiolabeled with a radioactive isotope such as C. All isotopic variations of the compounds, whether radioactive or not, are encompassed by the present invention.

[0053] It should be noted that throughout this application, options, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0054] "Analog" or "analogue" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0055] As used herein, the terms "a" or "an" mean one or more. Additionally, the phrase "substituted with a[n]" as used herein means that the specified group may be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C1-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is also substituted with one or more unsubstituted C1-C 20It may contain alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl groups.

[0056] When a moiety is substituted with one R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 1 The substituents are R 1A , R 1B can be distinguished from R 1A , R 1B etc. are R 1 are defined within the definition of and are optionally different.

[0057] As used herein, a "covalent cysteine ​​modifier moiety" refers to a substituent that can react with a sulfhydryl functional group of a cysteine ​​amino acid (e.g., cysteine ​​442 of interleukin-2 inducible T-cell kinase (ITK, TSK) (e.g., human interleukin-2 inducible T-cell kinase (ITK, TSK)) or the amino acid corresponding to cysteine ​​442 of interleukin-2 inducible T-cell kinase) to form a covalent bond. Thus, a covalent cysteine ​​modifier moiety is typically electrophilic.

[0058] The term "electrophilic chemical moiety" is used according to its plain and ordinary meaning to refer to a monovalent chemical group that is electrophilic.

[0059] The description of the compound is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to result in a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral, and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0060] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as argininate, and organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). In embodiments, the ITK inhibitors described herein are not in the form of a pharmaceutically acceptable salt.

[0061] Thus, the compounds may exist as salts with pharmaceutically acceptable acids, etc. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0062] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. Certain compounds may exist in unsolvated and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention.

[0063] ITK inhibitors An "interleukin-2-induced T cell kinase inhibitor" and an "ITK inhibitor" are compounds that negatively affect (e.g., decrease) the activity or function of interleukin-2-induced T cell kinase compared to the activity or function of interleukin-2-induced T cell kinase in the absence of the inhibitor (e.g., the ITK inhibitor binds to ITK).

[0064] ITK selectivity over RLK or BTK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 50-fold greater than its selectivity for resting lymphocyte kinase (RLK). In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 60-fold greater than its selectivity for RLK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 70-fold greater than its selectivity for RLK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 80-fold greater than its selectivity for RLK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 90-fold greater than its selectivity for RLK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 100-fold greater than its selectivity for RLK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 110-fold greater than its selectivity for RLK.

[0065] In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 50-fold greater than its selectivity for Bruton's tyrosine kinase (BTK). In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 60-fold greater than its selectivity for BTK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 70-fold greater than its selectivity for BTK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 80-fold greater than its selectivity for BTK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 90-fold greater than its selectivity for BTK. In some embodiments, the ITK inhibitor is a compound having selectivity for ITK that is at least 100-fold greater than its selectivity for BTK.

[0066] In embodiments, the ITK inhibitor is a compound described in U.S. Pat. No. 11,008,314. In embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is the free base form of a compound of Formula (I). In embodiments, the ITK inhibitor is the free base form of a compound of Formula (II). In embodiments, the ITK inhibitor is the free base form of a compound of Formula (A). In embodiments, the ITK inhibitor is a compound of Formulas (1)-(34) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is the free base form of a compound of Formulas (1)-(34).

[0067] In embodiments, the ITK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0068] [ka] wherein the substituents are as defined herein. In embodiments, the ITK inhibitor is any ITK inhibitor described in U.S. Patent No. 11,008,314, the disclosure of which is incorporated herein by reference in its entirety and for all purposes.

[0069] Ring A is

[0070] [ka] In some embodiments, ring A is

[0071] [ka] is.

[0072] In embodiments, the compound of formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0073] [ka] wherein the substituents are as defined herein.

[0074] R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, or -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1A , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -OR 1A , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0075] In some embodiments, R 1 and R 3 are each independently hydrogen, halogen, or -CX1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1A , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -OR 1A , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , or -NR 1A OR 1B is.

[0076] In embodiments, R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 In some embodiments, one or both of R 1 and R 3 One or both of the groups are hydrogen, methyl, ethyl, propyl, —CN, —COOH, —CONH 2 , —F, —Cl, —Br, or —I.

[0077] R 5 is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0078] In embodiments, R 5 is a substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), a substituted or unsubstituted heteroalkyl (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), a substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), a substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0079] In embodiments, R 5 is substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 5 is a substituted or unsubstituted (C1-C4) alkyl. In some embodiments, R 5 is unsubstituted (C1-C4) alkyl. In embodiments, R 5 is unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl. 5 is a substituted or unsubstituted 2-8 membered heteroalkyl. In some embodiments, R 5 is a substituted or unsubstituted 2-4 membered heteroalkyl. In some embodiments, R 5 is an unsubstituted 2-4 membered heteroalkyl. In some embodiments, R 5 is —CHN(CH). In embodiments, R 5 is a substituted or unsubstituted (C-C)cycloalkyl. In some embodiments, R 5 is unsubstituted (C-C)cycloalkyl. In embodiments, R 5 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl. 5 is a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted 5-6 membered heterocycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted 6-membered heterocycloalkyl. In some embodiments, R 5 is substituted or unsubstituted piperidinyl. In some embodiments, R 5 is substituted or unsubstituted phenyl. In some embodiments, R 5 is unsubstituted phenyl. In some embodiments, R 5 is 2-substituted phenyl. In some embodiments, R 5 is 3-substituted phenyl. In some embodiments, R 5is 4-substituted phenyl. In some embodiments, R 5 is phenyl substituted with halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 5 is phenyl substituted with halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 5 is —N(CH). In embodiments, R 5 is —NH(CH). In embodiments, R 5 is —N(CH2CH3)2. In embodiments, R 5 is —NH(CH2CH3). In embodiments, R 5 is —N(CH)(CHCH). In embodiments, R 5 is -CH3. In embodiments, R 5 is -CH2CH3. In embodiments, R 5 is unsubstituted isopropyl. In some embodiments, R 5 is unsubstituted tert-butyl.

[0080] In embodiments, R 5 is substituted or unsubstituted heteroaryl. In some embodiments, R 5 is a substituted or unsubstituted 5-6 membered heteroaryl. In some embodiments, R 5 is substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxazolyl, or substituted or unsubstituted isoxazolyl.

[0081] In embodiments, R 5 is substituted or unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R 5 is a substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted C6 cycloalkyl. In some embodiments, R 5 is a substituted or unsubstituted C5 cycloalkyl. In some embodiments, R 5 is substituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R 5 is a substituted C3-C8 cycloalkyl. In embodiments, R 5 is a substituted C-C cycloalkyl. In embodiments, R 5 is a substituted C5-C6 cycloalkyl. In embodiments, R 5 is a substituted C6 cycloalkyl. In embodiments, R 5 is a substituted C5 cycloalkyl. In embodiments, R 5 is unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R 5 is unsubstituted C-C cycloalkyl. In embodiments, R 5 is unsubstituted C-C cycloalkyl. In embodiments, R 5 is unsubstituted C5-C6 cycloalkyl. In embodiments, R 5 is an unsubstituted C6 cycloalkyl. In embodiments, R 5 is an unsubstituted C5 cycloalkyl.

[0082] In embodiments, R 5is substituted or unsubstituted aziridinyl, substituted or unsubstituted odilanyl, substituted or unsubstituted thiiranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted 1,2-dihydroazotyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted 2H-oxetyl, substituted or unsubstituted thietanyl, substituted or unsubstituted 2H-thiethyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted 2,5-dihydro-1H-pyrrolyl, substituted or unsubstituted 4,5-dihydro- In some embodiments, R is 1H-imidazolyl, substituted or unsubstituted imidazolinyl, substituted or unsubstituted pyrazolinyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted thiolanyl, substituted or unsubstituted piperdinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted 2H-pyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted 1,4-dioxanyl, tetrahydro-2H-pyranyl, substituted or unsubstituted thianyl, or substituted or unsubstituted dithianyl. 5 is substituted aziridinyl, substituted odilanyl, substituted thiiranyl, substituted azetidinyl, substituted 1,2-dihydroazotyl, substituted oxetanyl, substituted 2H-oxetyl, substituted thietanyl, substituted 2H-thiethyl, substituted pyrrolidinyl, substituted 2,5-dihydro-1H-pyrrolyl, substituted 4,5-dihydro-1H-imidazolyl, substituted imidazolinyl, substituted pyrazolinyl, substituted tetrahydrofuranyl, substituted thiolanyl, substituted piperidinyl, substituted piperazinyl, substituted 2H-pyranyl, substituted morpholinyl, substituted 1,4-dioxanyl, tetrahydro-2H-pyranyl, substituted thianyl, or substituted dithianyl. 5is unsubstituted aziridinyl, unsubstituted odilanyl, unsubstituted thiiranyl, unsubstituted azetidinyl, unsubstituted 1,2-dihydroazotyl, unsubstituted oxetanyl, unsubstituted 2H-oxetyl, unsubstituted thietanyl, unsubstituted 2H-thiethyl, unsubstituted pyrrolidinyl, unsubstituted 2,5-dihydro-1H-pyrrolyl, unsubstituted 4,5-dihydro-1H-imidazolyl, unsubstituted imidazolinyl, unsubstituted pyrazolinyl, unsubstituted tetrahydrofuranyl, unsubstituted thiolanyl, unsubstituted piperidinyl, unsubstituted piperazinyl, unsubstituted 2H-pyranyl, unsubstituted morpholinyl, unsubstituted 1,4-dioxanyl, tetrahydro-2H-pyranyl, unsubstituted thianil, or unsubstituted dithianil.

[0083] In embodiments, R 5 is substituted or unsubstituted (C6-C 10 ) aryl. In some embodiments, R 5 is substituted or unsubstituted phenyl. In some embodiments, R 5 is substituted or unsubstituted naphthyl. In some embodiments, R 5 is a substitution (C6~C 10 ) aryl. In some embodiments, R 5 is substituted phenyl. In some embodiments, R 5 is a substituted naphthyl. In embodiments, R 5 is unsubstituted (C6-C 10 ) aryl. In some embodiments, R 5 is unsubstituted phenyl. In some embodiments, R 5 is unsubstituted naphthyl.

[0084] In embodiments, R 5is imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted oxatriazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, or substituted or unsubstituted triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl). 5 is imidazolyl, substituted pyrrolyl, substituted pyrazolyl, substituted triazolyl, substituted tetrazolyl, substituted furanyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, substituted oxatriazolyl, substituted thienyl, substituted thiazolyl, substituted isothiazolyl, substituted pyridinyl, substituted pyrazinyl, substituted pyrimidinyl, substituted pyridazinyl, or substituted triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl). 5 is imidazolyl, unsubstituted pyrrolyl, unsubstituted pyrazolyl, unsubstituted triazolyl, unsubstituted tetrazolyl, unsubstituted furanyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, unsubstituted oxatriazolyl, unsubstituted thienyl, unsubstituted thiazolyl, unsubstituted isothiazolyl, unsubstituted pyridinyl, unsubstituted pyrazinyl, unsubstituted pyrimidinyl, unsubstituted pyridazinyl, or unsubstituted triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl).

[0085] In embodiments, R 5 teeth,

[0086] [ka] In some embodiments, R 5 teeth,

[0087] [ka] In some embodiments, R 5 teeth,

[0088] [ka] is.

[0089] In embodiments, R 5 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 5 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, R 5 is unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, R 5 is unsubstituted methyl. In some embodiments, R 5 is unsubstituted ethyl. In some embodiments, R 5 is unsubstituted propyl. In embodiments, R 5 is unsubstituted isopropyl. In some embodiments, R 5 is unsubstituted tert-butyl. In embodiments, R 5 is a substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5 is a substituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5 is an unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 5 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 5 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R5 is unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 5 is a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 5 is a substituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 5 is an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 5 is a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 5 is a substituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 5 is an unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 5 is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 5 is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 5 is unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0090] In embodiments, R 5 is substituted or unsubstituted pyrrolidinyl. In some embodiments, R 5 is substituted or unsubstituted tetrahydrofuranyl. In some embodiments, R 5 is substituted or unsubstituted imidazolidinyl. In embodiments, R 5 is substituted or unsubstituted pyrazolidinyl. In embodiments, R 5 is substituted or unsubstituted oxazolidinyl. In embodiments, R 5 is substituted or unsubstituted isoxazolidinyl. In embodiments, R 5is substituted or unsubstituted thiazolidinyl. In embodiments, R 5 is substituted or unsubstituted isothiazolidinyl. In embodiments, R 5 is substituted or unsubstituted dioxolanyl. In some embodiments, R 5 is substituted or unsubstituted dithiolanyl. In embodiments, R 5 is substituted or unsubstituted piperidinyl. In some embodiments, R 5 is substituted or unsubstituted oxanyl. In embodiments, R 5 is substituted or unsubstituted piperazinyl. In embodiments, R 5 is substituted or unsubstituted morpholinyl. In some embodiments, R 5 is substituted or unsubstituted pyridinyl. In some embodiments, R 5 is substituted or unsubstituted triazolyl. In embodiments, R 5 is substituted or unsubstituted tetrazolyl. In embodiments, R 5 is substituted or unsubstituted benzo[d][1,3]dioxolyl. In embodiments, R 5 is substituted or unsubstituted phenyl. In some embodiments, R 5 is substituted or unsubstituted pyridyl. In some embodiments, R 5 is substituted or unsubstituted pyridazinyl. In some embodiments, R 5 is substituted or unsubstituted pyrimidinyl. In some embodiments, R 5 is substituted or unsubstituted pyrazinyl. In some embodiments, R 5 is substituted or unsubstituted piperidinyl. In some embodiments, R 5 is substituted or unsubstituted tetrahydrofuranyl. In some embodiments, R 5 is substituted or unsubstituted tetrahydrothiopyranyl. In some embodiments, R 5 is substituted or unsubstituted cyclohexyl. In some embodiments, R 5 is substituted or unsubstituted cyclopentyl. In some embodiments, R 5 is substituted or unsubstituted cycloheptyl. In some embodiments, R 5 is substituted or unsubstituted cyclobutyl. In some embodiments, R5 is substituted or unsubstituted cyclopropyl. In some embodiments, R 5 is substituted or unsubstituted pyrrolyl. In some embodiments, R 5 is substituted or unsubstituted furanyl. In some embodiments, R 5 is substituted or unsubstituted thienyl. In some embodiments, R 5 is substituted or unsubstituted pyrazolyl. In some embodiments, R 5 is substituted or unsubstituted imidazolyl. In some embodiments, R 5 is substituted or unsubstituted isoxazolyl. In some embodiments, R 5 is substituted or unsubstituted oxazolyl. In embodiments, R 5 is substituted or unsubstituted isothiazolyl. In some embodiments, R 5 is substituted or unsubstituted thiazolyl. In embodiments, R 5 is substituted or unsubstituted naphthyl. In some embodiments, R 5 is substituted or unsubstituted quinolinyl. In some embodiments, R 5 is substituted or unsubstituted isoquinolinyl. In some embodiments, R 5 is a substituted or unsubstituted indolyl. In some embodiments, R 5 is substituted or unsubstituted benzimidazolyl. In embodiments, R 5 is substituted or unsubstituted indazolyl. In some embodiments, R 5 is a substituted or unsubstituted isoindolyl. In some embodiments, R 5 is substituted or unsubstituted benzofuranyl. In some embodiments, R 5 is substituted or unsubstituted benzo[c]thienyl. In some embodiments, R 5 is substituted or unsubstituted 2,3-dihydro-1H-indenyl. In embodiments, R 5 is substituted or unsubstituted 1,2,3,4-tetrahydronaphthyl. In embodiments, R 5 is substituted or unsubstituted triazolyl. In embodiments, R 5 is substituted or unsubstituted quinoxalinyl. In some embodiments, R 5is substituted or unsubstituted quinazolinyl. In some embodiments, R 5 is substituted or unsubstituted triazinyl. In some embodiments, R 5 is substituted or unsubstituted cinnolinyl. In some embodiments, R 5 is substituted or unsubstituted phthalazinyl. In some embodiments, R 5 is substituted or unsubstituted benzoxazolyl. In embodiments, R 5 is substituted or unsubstituted benzisoxazolyl. In embodiments, R 5 is substituted or unsubstituted benzothiazolyl. In embodiments, R 5 is substituted or unsubstituted benzisothiazolyl. In embodiments, R 5 is substituted or unsubstituted benzo[d][1,2,3]triazolyl. In embodiments, R 5 is a substituted or unsubstituted adamantyl.

[0091] L 1 is -O-, -S-, or substituted or unsubstituted C1-C2 alkylene, or substituted or unsubstituted 2-membered heteroalkylene. 1 In some embodiments, L 1 is -S-. In some embodiments, L 1 is a substituted C1-C2 alkylene. 1 is unsubstituted C1-C2 alkylene. In some embodiments, L 1 is a substituted 2-membered heteroalkylene. In embodiments, L 1 is an unsubstituted 2-membered heteroalkylene.

[0092] L 2 is a bond, —NH—, —C(O)NH—, or —NHC(O)—. 2 is a bond. In some embodiments, L 2 In some embodiments, L is —NH—. 2 is -NHC(O)-.

[0093] L 3 and L4 are each independently a bond, -S(O)2-, -N(R 6 )-, -O-, -S-, -C(O)-, -C(O)N(R 6 )-, -N(R 6 )C(O)-, -N(R 6 )C(O)NH-, -NHC(O)N(R 6 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0094] In embodiments, L 3 is a bond, -N(R 6 )-, -C(O)-, -C(O)N(R 6 )-, -N(R 6 )C(O)—, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), substituted or unsubstituted arylene (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroarylene (eg, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0095] In embodiments, L 3 is a bond, -N(R 6 )C(O)- or -C(O)N(R 6 )- and R 6 is hydrogen, -CX 6 3. -CHX 6 2. -CH2X 6 or unsubstituted (C1-C4) alkyl. In some embodiments, L 3 is a bond, -N(R 6 )C(O)- or -C(O)N(R6 )- and R 6 is hydrogen or unsubstituted methyl. In some embodiments, L 3 is a bond, —C(O)—, —C(O)N(CH)—, —N(CH)—, or —NH—. 3 is a bond. In some embodiments, L 3 is —C(O)—. In embodiments, L 3 is -N(R 6 In some embodiments, L 3 is —C(O)—. In embodiments, L 3 is -C(O)N(R 6 In some embodiments, L 3 In some embodiments, L is —NH—. 3 is —C(O)—. In embodiments, L 3 is —C(O)NH—. In embodiments, L 3 In some embodiments, L is —N(CH)—. 3 is —C(O)N(CH)—. In embodiments, L 3 is —N(CH2CH3)—. In some embodiments, L 3 is -C(O)N(CH2CH3)-.

[0096] In embodiments, L 3 is substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 3 is a substituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 3 is unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 3 is unsubstituted methylene. In some embodiments, L 3 is unsubstituted ethylene. In some embodiments, L 3 is unsubstituted propylene. In embodiments, L 3 is unsubstituted isopropylene. In some embodiments, L 3is unsubstituted tert-butylene. In embodiments, L 3 is a substituted or unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3 is a substituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3 is unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3 is a substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). 3 is a substituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). 3 is unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). 3 is a substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 3 is a substituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 3 is unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 3 is a substituted or unsubstituted arylene (e.g., C6-C 10 or phenylene). In some embodiments, L 3 is a substituted arylene (e.g., C6-C 10 or phenylene). In some embodiments, L 3 is an unsubstituted arylene (e.g., C6-C 10 or phenylene). In some embodiments, L 3 is substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 3is a substituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 3 is unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0097] In embodiments, L 3 is a bond, -S(O)2-, -N(R 6 )-, -O-, -S-, -C(O)-, -C(O)N(R 6 )-, -N(R 6 )C(O)-, -N(R 6 )C(O)NH-, -NHC(O)N(R 6 )-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), substituted or unsubstituted arylene (e.g., C6 to C 10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 3 is a bond, -S(O)2-, -N(R 6 )-, -O-, -S-, -C(O)-, -C(O)N(R 6 )-, -N(R 6 )C(O)-, -N(R 6 )C(O)NH-, -NHC(O)N(R 6 )-, -C(O)O-, -OC(O)-, unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), unsubstituted cycloalkylene (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), unsubstituted heterocycloalkylene (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), unsubstituted arylene (e.g., C6 to C10 or phenylene), or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 3 is unsubstituted methylene. In some embodiments, L 3 is unsubstituted ethylene. In some embodiments, L 3 is a methyl-substituted methylene.

[0098] In embodiments, L 4 is a bond, -N(R 6 )-, -C(O)-, -C(O)N(R 6 )-, -N(R 6 )C(O)—, substituted or unsubstituted alkylene (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered), substituted or unsubstituted arylene (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroarylene (eg, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0099] In embodiments, L 4 is a bond. In some embodiments, L 4 is -N(R 6 In some embodiments, L 4 is -C(O)N(R 6 In some embodiments, L 4 In some embodiments, L is —NH—. 4 is —C(O)—. In embodiments, L 4 is —C(O)NH—. In embodiments, L 4 In some embodiments, L is —N(CH)—. 4 is —C(O)N(CH)—. In embodiments, R 4 is —N(CH2CH3)—. In some embodiments, L 4is —C(O)N(CH2CH3)—. In embodiments, L 4 is a bond, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted fused-ring heterocycloalkylene, substituted or unsubstituted spirocyclic heterocycloalkylene, or substituted or unsubstituted bridged-ring heterocycloalkylene; and R 6 is hydrogen, -CX 6 3. -CHX 6 2. -CH2X 6 , or unsubstituted (C1-C4) alkyl.

[0100] In embodiments, L 4 is a bond, substituted or unsubstituted monocyclic heterocycloalkylene, substituted or unsubstituted fused-ring heterocycloalkylene, substituted or unsubstituted spirocyclic heterocycloalkylene, or substituted or unsubstituted bridged-ring heterocycloalkylene. 4 is an unsubstituted 7-8 membered bridged heterocycloalkylene. 4 is an unsubstituted 7-8 membered fused ring heterocycloalkylene. 4 is an unsubstituted 7-8 membered spirocyclic heterocycloalkylene. In some embodiments, L 4 is an unsubstituted 5-8 membered monocyclic heterocycloalkylene. 4 is a methyl-substituted 5-8 membered monocyclic heterocycloalkylene. 4 is a methyl-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is an ethyl-substituted 5-8 membered monocyclic heterocycloalkylene. 4 is an ethyl-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is a cyano-substituted 5- to 8-membered monocyclic heterocycloalkylene. 4 is a cyano-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4is halo-substituted 5-8 membered monocyclic heterocycloalkylene. 4 is halo-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is an unsubstituted 5-8 membered monocyclic heterocycloalkylene. 4 is an unsubstituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is an ethyl-substituted 5-8 membered monocyclic heterocycloalkylene. 4 is an ethyl-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is an isopropyl-substituted 5-8 membered monocyclic heterocycloalkylene. 4 is an isopropyl-substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is a tert-butyl substituted 5-8 membered monocyclic heterocycloalkylene. 4 is a tert-butyl substituted 6- to 7-membered monocyclic heterocycloalkylene. 4 is a substituted or unsubstituted 4- to 10-membered monocyclic heterocycloalkylene. 4 is a substituted or unsubstituted 5- to 8-membered monocyclic heterocycloalkylene. 4 is a substituted 5-8 membered monocyclic heterocycloalkylene. 4 is an unsubstituted 5-8 membered monocyclic heterocycloalkylene. 4 is a substituted or unsubstituted 5- to 10-membered fused ring heterocycloalkylene. 4 is a substituted or unsubstituted 7- to 8-membered fused ring heterocycloalkylene. 4 is a substituted 5- to 10-membered fused ring heterocycloalkylene. 4 is a substituted 7-8 membered fused ring heterocycloalkylene. 4 is an unsubstituted 5- to 10-membered fused ring heterocycloalkylene. 4is an unsubstituted 7-8 membered fused ring heterocycloalkylene. 4 is an unsubstituted 5-membered bridged heterocycloalkylene. 4 is an unsubstituted 6-membered bridged heterocycloalkylene. 4 is an unsubstituted 7-membered bridged heterocycloalkylene. 4 is an unsubstituted 8-membered bridged heterocycloalkylene. 4 is an unsubstituted 9-membered bridged heterocycloalkylene. 4 is an unsubstituted 10-membered bridged heterocycloalkylene. In embodiments, R 4 is an unsubstituted 5-membered bridged heterocycloalkylene. 4 is an unsubstituted 6-membered heterocycloalkylene. In some embodiments, L 4 is an unsubstituted 7-membered heterocycloalkylene. In embodiments, L 4 is an unsubstituted 8-membered heterocycloalkylene. In embodiments, L 4 is an unsubstituted 9-membered heterocycloalkylene. In embodiments, L 4 is an unsubstituted 10-membered heterocycloalkylene.

[0101] In embodiments, L 4 is substituted or unsubstituted cycloalkylene. In some embodiments, L 4 is a substituted or unsubstituted C3-C8 cycloalkylene. 4 is a substituted or unsubstituted C3-C6 cycloalkylene. 4 is a substituted or unsubstituted C5-C6 cycloalkylene. 4 is a substituted or unsubstituted C6 cycloalkylene. 4 is a substituted or unsubstituted C5 cycloalkylene. 4 is substituted cycloalkylene. In some embodiments, L 4 is a substituted C3-C8 cycloalkylene. 4is a substituted C3-C6 cycloalkylene. 4 is a substituted C5-C6 cycloalkylene. 4 is a substituted C6 cycloalkylene. In some embodiments, L 4 is a substituted C5 cycloalkylene. In embodiments, L 4 is unsubstituted cycloalkylene. In some embodiments, L 4 is unsubstituted C3-C8 cycloalkylene. In some embodiments, L 4 is unsubstituted C3-C6 cycloalkylene. In some embodiments, L 4 is unsubstituted C5-C6 cycloalkylene. 4 is an unsubstituted C6 cycloalkylene. In some embodiments, L 4 is an unsubstituted C5 cycloalkylene.

[0102] In embodiments, L 4 is a substituted or unsubstituted aziridinylene, substituted or unsubstituted odiranylene, substituted or unsubstituted thiiranylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted 1,2-dihydroazothylene, substituted or unsubstituted oxetanylene, substituted or unsubstituted 2H-oxetylene, substituted or unsubstituted thietanylene, substituted or unsubstituted 2H-thiethylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted 2,5-dihydro-1H-pyrrolylene, substituted or unsubstituted 4,5-dihydro-1H-imidazole In some embodiments, L is substituted or unsubstituted imidazolinylene, substituted or unsubstituted pyrazolinylene, substituted or unsubstituted tetrahydrofuranylene, substituted or unsubstituted thiolanylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted piperazinylene, substituted or unsubstituted 2H-pyranylene, substituted or unsubstituted morphonylene, substituted or unsubstituted 1,4-dioxanylene, substituted or unsubstituted tetrahydro-2H-pyranylene, substituted or unsubstituted thianylene, or substituted or unsubstituted dithianylene. 4is a substituted aziridinylene, substituted aziranylene, substituted thiiranylene, substituted azetidinylene, substituted 1,2-dihydroazotylene, substituted oxetanylene, substituted 2H-oxetylene, substituted thietanylene, substituted 2H-thiethylene, substituted pyrrolidinylene, substituted 2,5-dihydro-1H-pyrrolylene, substituted 4,5-dihydro-1H-imidazolylene, substituted imidazolinylene, substituted pyrazolinylene, substituted tetrahydrofuranylene, substituted thiolanylene, substituted piperidinylene, substituted piperazinylene, substituted 2H-pyranylene, substituted morpholinylene, substituted 1,4-dioxanylene, substituted tetrahydro-2H-pyranylene, substituted thianylene, or substituted dithianylene. 4 is unsubstituted aziridinylene, unsubstituted odilanylene, unsubstituted thiiranylene, unsubstituted azetidinylene, unsubstituted 1,2-dihydroazotylene, unsubstituted oxetanylene, unsubstituted 2H-oxetylene, unsubstituted thietanylene, unsubstituted 2H-thiethylene, unsubstituted pyrrolidinylene, unsubstituted 2,5-dihydro-1H-pyrrolylene, unsubstituted 4,5-dihydro-1H-imidazolylene, unsubstituted imidazolinylene, unsubstituted pyrazolinylene, unsubstituted tetrahydrofuranylene, unsubstituted thiolanylene, unsubstituted piperidinylene, unsubstituted piperazinylene, unsubstituted 2H-pyranylene, unsubstituted morphonylene, unsubstituted 1,4-dioxanylene, unsubstituted tetrahydro-2H-pyranylene, unsubstituted thianylene, or unsubstituted dithianylene.

[0103] In embodiments, L 4 is substituted or unsubstituted (C6-C 10 In some embodiments, L 4 is substituted or unsubstituted phenylene. In some embodiments, L 4 is substituted or unsubstituted naphthylene. In some embodiments, L 4 is a substitution (C6~C 10 In some embodiments, L 4 is unsubstituted phenylene. In some embodiments, L 4 is unsubstituted naphthylene. In embodiments, L 4 is unsubstituted (C6-C 10 In some embodiments, L4 is unsubstituted phenylene. In some embodiments, L 4 is unsubstituted naphthylene.

[0104] In embodiments, L 4 is substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted triazolylene, substituted or unsubstituted tetrazolylene, substituted or unsubstituted furanylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted isoxazolylene, substituted or unsubstituted oxadiazolylene, substituted or unsubstituted oxatriazolylene, substituted or unsubstituted thienylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted isothiazolylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted pyrimidinylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted triazinylene (e.g., 1,3,5-triazinylene, 1,2,3-triazinylene, or 1,2,4-triazinylene). 4 is a substituted imidazolylene, substituted pyrrolylene, substituted pyrazolylene, substituted triazolylene, substituted tetrazolylene, substituted furanylene, substituted oxazolylene, substituted isoxazolylene, substituted oxadiazolylene, substituted oxatriazolylene, substituted thienylene, substituted thiazolylene, substituted isothiazolylene, substituted pyridinylene, substituted pyrazinylene, substituted pyrimidinylene, substituted pyridazinylene, or substituted triazinylene (e.g., 1,3,5-triazinylene, 1,2,3-triazinylene, or 1,2,4-triazinylene). 4is unsubstituted imidazolylene, unsubstituted pyrrolylene, unsubstituted pyrazolylene, unsubstituted triazolylene, unsubstituted tetrazolylene, unsubstituted furanylene, unsubstituted oxazolylene, unsubstituted isoxazolylene, unsubstituted oxadiazolylene, unsubstituted oxatriazolylene, unsubstituted thienylene, unsubstituted thiazolylene, unsubstituted isothiazolylene, unsubstituted pyridinylene, unsubstituted pyrazinylene, unsubstituted pyrimidinylene, unsubstituted pyridazinylene, or unsubstituted triazinylene (e.g., 1,3,5-triazinylene, 1,2,3-triazinylene, or 1,2,4-triazinylene).

[0105] In embodiments, L 4 teeth,

[0106] [ka] In some embodiments, L 4 teeth,

[0107] [ka] In some embodiments, L 4 teeth,

[0108] [ka] In some embodiments, L 4 teeth,

[0109] [ka] In some embodiments, L 4 teeth,

[0110] [ka] In some embodiments, L 4 teeth,

[0111] [ka] In some embodiments, L 4 teeth,

[0112] [ka] In some embodiments, L 4 teeth,

[0113] [ka] In some embodiments, L 4 teeth,

[0114] [ka] In some embodiments, L 4 teeth,

[0115] [ka] In some embodiments, L 4 teeth,

[0116] [ka] In some embodiments, L 4 teeth,

[0117] [ka] In some embodiments, L 4 teeth,

[0118] [ka] is.

[0119] R 6 are independently hydrogen, -CX 6 3. -CHX 6 2. -CH2X 6, -CN, -C(O)R 6A , -C(O)OR 6A , -C(O)NR 6A R 6B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0120] In embodiments, R 6 are independently hydrogen, -CX 6 3. -CHX 6 2. -CH2X 6 , -CN, -C(O)R 6A , -C(O)-OR 6A , -C(O)NR 6A R 6B , substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0121] In embodiments, R 6 is hydrogen. In some embodiments, R 6 -CX 6 3. In embodiments, R 6 -CHX 6 2. In embodiments, R 6 is -CH2X 6 In some embodiments, R 6 is -CN. In embodiments, R 6 is -C(O)R 6A In some embodiments, R 6 is -C(O)-OR6A In some embodiments, R 6 is -C(O)NR 6A R 6B In some embodiments, R 6 is —COOH. In embodiments, R 6 is -CONH2. In embodiments, R 6 is —CF3. In embodiments, R 6 is -CHF2. In embodiments, R 6 is —CHF. In embodiments, R 6 is -CH3. In embodiments, R 6 is -CH2CH3. In embodiments, R 6 is -CH2CH2CH3. In embodiments, R 6 is —CH(CH) . In embodiments, R 6 is -C(CH3)3.

[0122] In embodiments, R 6 is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 6 is a substituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, R 6 is unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). In some embodiments, R 6 is unsubstituted methyl. In some embodiments, R 6 is unsubstituted ethyl. In some embodiments, R 6 is unsubstituted propyl. In embodiments, R 6 is unsubstituted isopropyl. In some embodiments, R 6 is unsubstituted tert-butyl. In embodiments, R 6 is a substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6 is a substituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered).6 is an unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 6 is a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 6 is a substituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 6 is unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 6 is a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 6 is a substituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 6 is an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 6 is a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 6 is a substituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 6 is an unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 6 is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 6 is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 6 is unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0123] E is an electrophilic moiety. In embodiments, E is a covalent cysteine ​​modifier moiety. In embodiments, E is

[0124] [ka] In embodiments, E is

[0125] [ka] In embodiments, E is

[0126] [ka] In embodiments, E is

[0127] [ka] In embodiments, E is

[0128] [ka] In embodiments, E is -C(O)CH=CH2, -C(O)CH=CHCH2N(CH3)2, -C(O)C(=CH2)CH2N(CH3)2,

[0129] [ka] Or -C(O)C(=CH2)CH3.

[0130] Each R 1A , R 1B , R 6A , and R 6B are each independently hydrogen, -CX, -CN, -COOH, -CONH, -CHX, -CHX, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 1A and R 1BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 6A and R 6B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0131] In embodiments, R 1A , R 1B , R 6A , and R 6B are each independently hydrogen, -CX 1A 3. -CHX 1A 2. -CH2X 1A , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1A , R 1B , R 6A and R 6B are each independently hydrogen, -CX 1A 3. -CHX 1A 2. -CH2X 1A , -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1A is -F, -Cl, -Br, or -I.

[0132] In embodiments, R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B One or more of the -CX 6 3. In embodiments, R 1A , R 1B , R 6A , and R 6B One or more of the -CHX 6 2. In embodiments, R 1A , R 1B , R 6A , and R 6B At least one of the following is -CH2X 6 In some embodiments, R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B At least one of the groups is -CONH2.

[0133] In embodiments, R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 1A , R 1B , R 6A , and R6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B is unsubstituted tert-butyl. 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is a substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is a substituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 1B , R 6A , and R 6BIn some embodiments, one or more of R is an unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is a substituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 1A , R 1B , R 6A , and R 6B At least one of the groups may be substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 1A , R 1B , R 6A , and R6B At least one of the groups may be a substituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 1A , R 1B , R 6A , and R 6B At least one of the groups is an unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R is substituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1A , R 1B , R 6A , and R 6B At least one of is unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0134] In embodiments, R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6BIn some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B In some embodiments, one or more of R 1A , R 1B , R 6A , and R 6B One or more of is -F, -Cl, -Br, or -I.

[0135] X, X 1 , X 1A , X 6 , and X 15 are each independently -F, -Cl, -Br, or -I. In embodiments, X is -F. In embodiments, X is -Cl. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F. 1 is -F. In some embodiments, X 1 In some embodiments, X is —Cl. 1 In some embodiments, X is -Br. 1 In some embodiments, X is -I. 1A is -F. In some embodiments, X 1A In some embodiments, X is —Cl. 1A In some embodiments, X is -Br. 1A In some embodiments, X is -I. 6 is -F. In some embodiments, X 6 In some embodiments, X is —Cl. 6 In some embodiments, X is -Br. 6 In some embodiments, X is -I. 15 is -F. In some embodiments, X 15 In some embodiments, X is —Cl. 15 In some embodiments, X is -Br. 15 is -I.

[0136] Each n1 is independently an integer of 0 to 4. In multiple embodiments, n1 is 0. In multiple embodiments, n1 is 1. In multiple embodiments, n1 is 2. In multiple embodiments, n1 is 3. In multiple embodiments, n1 is 4.

[0137] m1 is independently 1 or 2. In some embodiments, m1 is 1. In some embodiments, m1 is 2.

[0138] v1 is independently 1 or 2. In some embodiments, v1 is 1. In some embodiments, v1 is 2.

[0139] R 15 , R 16 , and R 17 are each independently hydrogen, halogen, or -CX 15 3. -CHX 15 2. -CH2X 15 , -CN, -SO n15 R 15A , -SO v15 NR 15A R 15B , -NHNR 15A R 15B , -ONR 15A R 15B , -NHC=(O)NHNR 15A R 15B , -NHC(O)NR 15A R 15B , -N(O) m15 , -NR 15A R 15B , -C(O)R 15A , -C(O)-OR 15A , -C(O)NR 15A R 15B , -OR 15A , -NR 15A SO2R 15B , -NR 15A C(O)R 15B , -R 15A C(O)OR 15B , -NR 15A OR 15B , -OCX 15 3. -OCHX 15 2, -OCH2X15 , substituted or unsubstituted alkyl (e.g., C 1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0140] In embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 One or more of the -CX 15 3. In embodiments, R 15 , R 16 , and R 17 At least one of the following is -CHX 15 2. In embodiments, R 15 , R 16 , and R 17 At least one of the following is -CH2X 15 In some embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 One or more of the -SO n15 R 15A In some embodiments, R 15 , R 16 , and R 17 One or more of the -SO v15 NR15A R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NHNR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 One or more of the following is -ONR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NHC=(O)NHNR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NHC(O)NR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the following is -N(O) m15 In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -C(O)R 15A In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -C(O)-OR 15A In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is —C(O)NR 15A R 15B In some embodiments, R 15 , R 16 , and R 17 One or more of the following can be -OR 15A In some embodiments, R15 , R 16 , and R 17 At least one of the groups is -NR 15A SO2R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NR 15A C(O)R 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NR 15A C(O)OR 15B In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is -NR 15A OR 15B In some embodiments, R 15 , R 16 , and R 17 One or more of the following must be -OCX 15 3. In embodiments, R 15 , R 16 , and R 17 At least one of the following must be -OCHX 15 2. In embodiments, R 15 , R 16 , and R 17 One or more of the following is -OCH2X 15 In some embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 One or more of is -I.

[0141] In embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 is R 16 , and R 17 In some embodiments, one or more of R is a substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R is a substituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15 , R 16 , and R 17In some embodiments, one or more of R is an unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 is unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6). In embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R is a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R is a substituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R is an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15 , R 16 , and R 17 At least one of the groups may be substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 15 , R 16 , and R 17 At least one of the groups may be a substituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 15 , R 16 , and R 17 At least one of the groups is an unsubstituted aryl (e.g., C6-C 10or phenyl). In some embodiments, R 15 , R 16 , and R 17 In some embodiments, one or more of R is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R is substituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15 , R 16 , and R 17 One or more of is unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0142] In embodiments, R 15 , R 16 , and R 17 are each independently hydrogen, halogen, or -CX 15 3. -CHX 15 2. -CH2X 15 , -OCX 15 3. -OCH2X 15 , -OCHX 15 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, R 15A substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), and in embodiments, R 15 , R 16 , and R 17 are each independently hydrogen, halogen, or -CX 15 3. -CHX 15 2. -CH2X 15 , -OCX 15 3. -OCH2X 15 , -OCHX 152, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 In some embodiments, one or more of R 15 , R 16 , and R 17 is unsubstituted ethyl.

[0143] In embodiments, R 15 , R 16 , and R 17 is hydrogen. In some embodiments, R 15 is hydrogen. In some embodiments, R 16 is hydrogen, -CH3, or -CH2NR 15A R 15B In some embodiments, R 17 is hydrogen. In some embodiments, R 15A and R 15B is independently hydrogen or unsubstituted alkyl. In some embodiments, R 15A and R 15B is independently unsubstituted methyl. In some embodiments, R 15A is hydrogen. In some embodiments, R 15Ais unsubstituted alkyl. In embodiments, R 15B is hydrogen. In some embodiments, R 15B is unsubstituted alkyl. In embodiments, R 15A is unsubstituted methyl. In some embodiments, R 15B is unsubstituted methyl. In some embodiments, R 15 is hydrogen and R 16 is hydrogen, -CH3, or -CH2NR 15A R 15B and R 17 is hydrogen and R 15A and R 15B is independently hydrogen or unsubstituted alkyl.

[0144] In embodiments, R 15 is hydrogen. In some embodiments, R 16 is hydrogen. In some embodiments, R 17 is hydrogen, -CH3, or -CH2NR 15A R 15B In some embodiments, R 15A and R 15B is independently hydrogen or unsubstituted alkyl. In some embodiments, R 15A and R 15B is independently unsubstituted methyl. In some embodiments, R 15 is hydrogen and R 16 is hydrogen and R 17 is hydrogen, -CH3, or -CH2NR 15A R 15B and R 15A and R 15B is independently hydrogen or unsubstituted alkyl. In some embodiments, R 15A is hydrogen. In some embodiments, R 15A is unsubstituted alkyl. In embodiments, R 15B is hydrogen. In some embodiments, R 15B is unsubstituted alkyl. In embodiments, R 15A is unsubstituted methyl. In some embodiments, R 15B is unsubstituted methyl.

[0145] In embodiments, R 15 is hydrogen, -CH3, or -CH2NR 15A R 15B In some embodiments, R 16 is hydrogen. In some embodiments, R 17 is hydrogen. In some embodiments, R 15A and R 15B is independently hydrogen or unsubstituted alkyl. In some embodiments, R 15A and R 15B is independently unsubstituted methyl. In some embodiments, R 15A is hydrogen. In some embodiments, R 15A is unsubstituted alkyl. In embodiments, R 15B is hydrogen. In some embodiments, R 15B is unsubstituted alkyl. In embodiments, R 15A is unsubstituted methyl. In some embodiments, R 15B is unsubstituted methyl. In some embodiments, R 15 is hydrogen, -CH3, or -CH2NR 15A R 15B and R 16 is hydrogen and R 17 is hydrogen and R 15A and R 15B is independently hydrogen or unsubstituted alkyl.

[0146] R 15A and R 15B are each independently hydrogen, -CX, -CN, -COOH, -CONH, -CHX, -CHX, substituted or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, C1 to C4, or C1 to C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members), substituted or unsubstituted cycloalkyl (e.g., C3 to C8, C3 to C6, C4 to C6, or C5 to C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, 4 to 6 members, 4 to 5 members, or 5 to 6 members), substituted or unsubstituted aryl (e.g., C6 to C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15A and R 15B The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0147] In embodiments, R 15A and R 15B In some embodiments, one or both of R 15A and R 15B One or both of the following may be -CX 15A 3. In embodiments, R 15A and R 15B One or both of the groups may be -CHX 15A 2. In embodiments, R 15A and R 15B One or both of the following may be -CH2X 15A In some embodiments, R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B One or both of is -CONH2.

[0148] In embodiments, R 15A and R 15B In some embodiments, one or both of R is substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R is unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). 15Aand R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R is substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15A and R 15B In some embodiments, one or both of R is a substituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15A and R 15B In some embodiments, one or both of R is unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). 15A and R 15B In some embodiments, one or both of R is substituted or unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C). 15A and R 15B In some embodiments, one or both of R is substituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C). 15A and R 15B In some embodiments, one or both of R is unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C). 15A and R 15B In some embodiments, one or both of R is a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15A and R 15BIn some embodiments, one or both of R is a substituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15A and R 15B In some embodiments, one or both of R is an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered). 15A and R 15B One or both of may be substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 15A and R 15B One or both of the groups may be substituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 15A and R 15B One or both of the groups may be unsubstituted aryl (e.g., C6-C 10 or phenyl). In some embodiments, R 15A and R 15B In some embodiments, one or both of R is substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15A and R 15B In some embodiments, one or both of R 15A and R 15B One or both of is unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0149] In embodiments, R 15A and R 15B are each independently hydrogen, -CX 15A 3. -CHX 15A 2. -CH2X 15A , -CN, -COOH, -CONH2, and in embodiments, R 15A and R 15B are each independently hydrogen, -CX 15A 3. -CHX 15A 2. -CH2X 15A, -CN, -COOH, -CONH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15A is independently -F, -Cl, -Br, or -I. In embodiments, R 15A and R 15B In some embodiments, one or both of R 15A and R 15B In some embodiments, one or both of R 15A and R 15B One or both of is unsubstituted ethyl.

[0150] n15 is independently an integer from 0 to 4. In multiple embodiments, n15 is 0. In multiple embodiments, n15 is 1. In multiple embodiments, n15 is 2. In multiple embodiments, n15 is 3. In multiple embodiments, n15 is 4.

[0151] v15 is 1 or 2. In some embodiments, v15 is 1. In some embodiments, v15 is 2.

[0152] m15 is 1 or 2. In some embodiments, m15 is 1. In some embodiments, m15 is 2.

[0153] In embodiments, the compound of formula (I) is a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0154] [ka]

[0155] In embodiments, the compound of Formula (I) is a compound of any one of Formulas (1) through (34), or a pharmaceutically acceptable salt of any one of the foregoing:

[0156] [ka]

[0157] [ka]

[0158] [ka]

[0159] [ka]

[0160] Methods for making the ITK inhibitors described herein are described in US Pat. No. 11,008,314, the disclosure of which is incorporated herein by reference in its entirety.

[0161] Treatment method The terms "treating" and "treatment" refer to any indication of success in therapy or improvement of a disease, condition, or disease, and include any objective or subjective parameter, such as relief, remission, reduction in symptoms, or making the disease or condition more tolerable for the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical or mental well-being, etc. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical exam. The term "treating" and its conjugations can include prevention of a disease, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0162] As used herein (and as is well understood in the art), "treating" or "treatment" broadly includes any approach to obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or total, and whether detectable or undetectable, reduction in the extent of disease, stabilization of disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or relief of disease state, reduction in disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of disease. Treatment can prevent disease from occurring, inhibit the spread of disease, alleviate symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten disease duration, or a combination thereof.

[0163] As used herein, "treating" and "treatment" include prophylactic treatment. A therapeutic method involves administering a therapeutically effective amount of an ITK inhibitor to a subject. The administering step can consist of a single administration or can include a series of administrations. The length of treatment depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the ITK inhibitor, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of an ITK inhibitor used for treatment or prevention may increase or decrease during a particular treatment or prevention regimen. Modifications in dosage can be effected and made evident by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, a composition is administered to a subject in an amount and for a duration sufficient to treat the patient. In some embodiments, the treating or treatment is not prophylactic.

[0164] "Patient" or "subject" refers to a mammal suffering from or susceptible to a disease (e.g., cancer) that can be treated by administration of a compound or pharmaceutical composition or by a method as provided herein. Non-limiting examples of patients include humans, cows, rats, mice, dogs, cats, monkeys, goats, sheep, etc. In embodiments, the patient is a human. In embodiments, the patient is a dog or cat. In embodiments, the patient is a human adult. In embodiments, the patient is a human child.

[0165] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route compatible with the preparation, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In some embodiments, administration does not include administration of any active agents other than the listed active agents.

[0166] "Biological sample" or "sample" refers to a material obtained or derived from a subject or patient. Biological samples include tissue sections, such as biopsies. Such samples include bodily fluids (e.g., blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, etc.), sputum, tissues, cultured cells (e.g., primary cultures, explants, and transformed cells), feces, urine, etc.). In embodiments, the biological sample is blood. In embodiments, the biological sample is tumor cells. In embodiments, the biological sample is a tumor.

[0167] The term "biomarker" refers to an indicator, e.g., a predictive, prognostic, and / or pharmacodynamic indicator, that can be detected in a biological sample. A biomarker can serve as an indicator of the likelihood that a patient will respond to a particular therapeutic treatment or a particular subtype of a disease or disorder characterized by certain molecular, pathological, histological, and / or clinical characteristics. In some embodiments, the biomarker is a cytokine. In some embodiments, the biomarker is a gene or set of genes (i.e., biomarker genes). Biomarkers include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polynucleotide copy number changes (e.g., DNA copy number), polypeptides, or polypeptide and polynucleotide modifications (e.g., post-translational modifications). In some embodiments, the biomarker is LAG3, TIGIT, PD-1, IFNγ, or granzyme B.

[0168] The term "increased expression level" or "increased level" of gene expression is an expression level of a gene that is higher than the expression level of the gene in a control. The control can be any control known in the art, such as those described herein. In embodiments, an "increased level" of a biomarker gene compared to a control (where the biomarker expression level is higher than the corresponding control) is, for example, about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% or more increase in expression level compared to the control. In embodiments, an "increased level" of a biomarker gene is an amount that is statistically significantly greater than the expression level of the control.

[0169] The term "decreased expression level" or "decreased level" of gene expression is an expression level of a gene that is lower than the expression level of the gene in a control. The control can be any control known in the art, such as those described herein. In embodiments, a "decreased level" of a biomarker gene compared to a control (where the biomarker expression level is lower than the corresponding control) is, for example, about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% or more decrease in expression level compared to the control. In embodiments, a "decreased level" of a biomarker gene is an amount that is statistically significantly less than the expression level of the control.

[0170] "Control" is used according to its plain and ordinary meaning to refer to an assay, comparison, or experiment in which an experimental subject or reagent is treated identically to a parallel experiment except for the omission of an experimental procedure, reagent, or variable. In embodiments, a control is used as a standard of comparison in assessing experimental efficacy. In embodiments, a control is a gene expression level to which another gene expression level (e.g., a gene expression level of a biomarker gene disclosed herein) is compared (e.g., to make a diagnostic (e.g., predictive and / or prognostic) and / or therapeutic decision).

[0171] In some embodiments, the control is a healthy patient or a population of healthy patients. In some embodiments, the healthy patient is a patient without cancer. In some embodiments, the control is an average value from a population of healthy patients. In some embodiments, the control is a pre-assigned value, e.g., a cut-off value previously determined to significantly separate a first group of patients (e.g., cancer patients with T cell exhaustion) from a second group of patients (e.g., cancer patients without T cell exhaustion). In some embodiments, the cut-off value is the median or average (preferably the median) gene expression level in a reference population. A control can also be obtained from the same individual, e.g., from an earlier sample, before disease, or before treatment. Those skilled in the art will recognize that a control can be designed for evaluation of any number of parameters. In some embodiments, the control is a negative control. In some embodiments, such as some embodiments relating to detection of expression levels of a gene / protein or a subset of genes / proteins, the control comprises the average expression amount (e.g., protein or mRNA) in a subject population (e.g., with cancer) or in a healthy or general population. In some embodiments, the control comprises the average amount (e.g., expression level) in a population where the number of subjects (n) is 5 or more, 20 or more, 50 or more, 100 or more, 1000 or more, etc. One of skill in the art will know which control would be useful in a given situation and will be able to analyze data based on comparison to the control value.

[0172] Biomarker levels can be detected at either the protein (e.g., cytokine) or gene expression level. Proteins expressed by biomarkers can be quantified by immunohistochemistry (IHC), ELISA, or flow cytometry using antibodies to detect the proteins. Biomarker expression can be quantified by several platforms known in the art. Quantifying biomarker (gene) expression can alternatively be referred to as detecting biomarker (gene) expression levels. Platforms that can be used to quantify biomarker (gene) expression or detect biomarker (gene) expression levels include quantitative polymerase chain reaction (qPCR), multiplex quantitative polymerase chain reaction (multiplex qPCR), real-time polymerase chain reaction (rtPCR), Nanostring (e.g., an amplification-free technique that measures nucleic acid content by directly counting molecules), RNA sequencing (using next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample), or in situ hybridization. Biomarker expression, as measured by Nanostring, varies widely. In embodiments, quantitative rtPCR, Nanostring, RNA sequencing (RNAseq), and in situ hybridization are used to quantify biomarker gene expression. In embodiments, biomarker expression is quantified by RNAseq. In embodiments, biomarker expression is quantified by multiplex qPCR. In embodiments, biomarker expression is quantified by NanoString. With Nanostring, RNA is extracted from a biological sample, and a known amount of RNA is placed in a Nanostring instrument to detect gene expression using gene-specific probes.The number of biomarker counts in the sample is determined and normalized to a set of housekeeping genes. To determine the threshold for elevated or decreased biomarker levels, one skilled in the art could evaluate biomarker levels in a control group of samples and select the 10th, 20th, 25th, 30th, 40th, 50th, 60th, 70th, 75th, 80th, or 90th percentile of biomarker gene expression. In some embodiments, increased or decreased biomarker expression can be determined by calculating an H-score for biomarker expression. Thus, increased or decreased biomarker expression can have an H-score. As used herein, "H-score" or "histoscore" is a numerical value determined by commonly known semi-quantitative methods for immunohistochemically assessing protein expression in tumor samples.

[0173] The present disclosure provides methods of treating a patient with deficient Th1 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the patient has increased Th2 activity. In embodiments, the patient has increased pro-inflammatory cytokine levels. In embodiments, the patient has increased levels of a pro-inflammatory cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, and combinations of two or more thereof. In embodiments, the patient has increased levels of a pro-inflammatory cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, IL-17, and combinations of two or more thereof. In embodiments, the effective amount to increase Th1 activity is an amount that increases Th1 activity. + Increases the number of T cells, Th2 + Th1 vs. T cells + Increases the ratio of T cells to IL-4 + CD4 + IFNγ on T cells + CD4 +In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that increases the ratio of Th1 T cells, increases IFNγ production, increases CD8+ cytotoxic lymphocytes, inhibits IL-4 production, inhibits IL-5 production, inhibits IL-13 production, decreases Th2+ cells, decreases Th17+ T cells, decreases eosinophils, or a combination of two or more of the foregoing. + Increases the number of T cells, Th2 + Th1 vs. T cells + Increases the ratio of T cells to IL-4 + CD4 + IFNγ on T cells + CD4 + In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that increases the ratio of Th1 T cells, increases IFNγ production, increases CD8+ cytotoxic lymphocytes, inhibits IL-4 production, decreases Th17+ T cells, decreases eosinophils, or a combination of two or more of the foregoing. + Increase the number of T cells or Th2 + Th1 vs. T cells + Increase the ratio of T cells or IL-4 + CD4 + IFNγ on T cells + CD4 + In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that increases the ratio of Th1 T cells, increases IFNγ production, increases CD8+ cytotoxic lymphocytes, inhibits IL-4 production, decreases Th17+ T cells, decreases eosinophils, inhibits Th2, or inhibits differentiation of naive CD4+ cells into Th2 cells, or a combination of two or more of the foregoing. + In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that increases the number of T cells. + Th1 vs. T cells + In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that increases the ratio of T cells to IL-4. +CD4 + IFNγ on T cells + CD4 + In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that increases the ratio of T cells to T cells. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that increases IFN-γ production. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that increases CD8+ cytotoxic lymphocytes. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits IL-4 production. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits IL-5 production. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits IL-13 production. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits cytokines secreted by Th2+ cells. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that reduces Th2+ cells. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that reduces Th17+ T cells. In some embodiments, the effective amount for increasing Th1 activity is the amount of an ITK inhibitor that reduces eosinophils. In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that blocks Th2 or blocks the differentiation of naive CD4 cells into Th2 cells. In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that inhibits Th2. In some embodiments, an effective amount for increasing Th1 activity is an amount of an ITK inhibitor that inhibits the differentiation of naive CD4 cells into Th2 cells. In some embodiments, an effective amount for increasing Th1 activity is about 0.5 millimoles to about 2 millimoles of an ITK inhibitor per day. In some embodiments, "deficient Th1 activity" is Th1 activity that is reduced compared to a control. In some embodiments, the control is a healthy patient or a population of healthy patients.

[0174] The present disclosure provides a method of treating a patient with deficient Th1 activity by (i) measuring increased levels of Th2 activity in a biological sample from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method of treating a patient with deficient Th1 activity by (i) measuring increased levels of a cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, IL-17, and a combination of two or more thereof in a biological sample from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method of treating a patient with deficient Th1 activity by (i) measuring increased levels of IL-4 in a biological sample from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method for treating a patient with deficient Th1 activity by (i) measuring increased IL-5 levels in a biological sample from the patient compared to a control and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method for treating a patient with deficient Th1 activity by (i) measuring increased IL10 levels in a biological sample from the patient compared to a control and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method for treating a patient with deficient Th1 activity by (i) measuring increased IL-13 levels in a biological sample from the patient compared to a control and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. The present disclosure provides a method for treating a patient with deficient Th1 activity by (i) measuring increased IL-17 levels in a biological sample from the patient compared to a control and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In several embodiments, the patient has increased Th2 activity. In embodiments, the patient has elevated pro-inflammatory cytokine levels.In some embodiments, the patient has increased levels of a pro-inflammatory cytokine selected from the group consisting of IL-4, IL-5, IL10, IL-13, and combinations of two or more thereof. In some embodiments, the effective amount for increasing Th1 activity is a Th1. + Increase the number of T cells or Th2 + Th1 vs. T cells + Increase the ratio of T cells or IL-4 + CD4 + IFNγ on T cells + CD4 + The effective amount for increasing Th1 activity is the amount of an ITK inhibitor that increases the ratio of T cells, increases IFNγ production, increases CD8+ cytotoxic lymphocytes, inhibits IL-4 production, decreases Th17+ T cells, decreases eosinophils, inhibits Th2, or inhibits the differentiation of naive CD4 cells into Th2 cells, or a combination of two or more of the foregoing. In some embodiments, an effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits Th2 or inhibits the differentiation of naive CD4 cells into Th2 cells. In some embodiments, an effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits Th2. In some embodiments, an effective amount for increasing Th1 activity is the amount of an ITK inhibitor that inhibits the differentiation of naive CD4 cells into Th2 cells.

[0175] In embodiments, the present disclosure provides a method of treating a patient with deficient Th1-type cytokines by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with increased Th2 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with deficient Th1 activity and increased Th2 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with increased pro-inflammatory cytokine levels by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with deficient Th1 activity and increased pro-inflammatory cytokine levels by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, "defective Th1-type cytokines" refers to decreased Th1 levels of Th1-type cytokines. In embodiments, Th1-type cytokines include IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, and granulocyte-macrophage colony-stimulating factor (GMCS). In embodiments, "increased Th2 activity" is increased Th2 activity compared to a control. In embodiments, "increased pro-inflammatory cytokine levels" are compared to a control. In embodiments, the "pro-inflammatory cytokine" is IL-4, IL-5, IL10, IL-13, or a combination of two or more thereof. In embodiments, the "pro-inflammatory cytokine" is IL-4, IL-5, IL10, IL-13, IL-17, or a combination of two or more thereof. In embodiments, the control is a healthy patient or a healthy patient population.In some embodiments, the present disclosure provides a method for treating a patient with deficient Th1-type cytokines by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In some embodiments, the present disclosure provides a method for treating a patient with deficient Th1-type cytokines by (i) measuring decreased levels of Th1, IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, GMCS, or a combination of two or more thereof in a biological sample from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In some embodiments, the present disclosure provides a method for treating a patient with deficient Th1-type cytokines by (i) measuring increased levels of IL-4, IL-5, IL10, IL-13, IL-17, or a combination of two or more thereof in a biological sample from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with increased Th2 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with increased Th2 activity by (i) measuring increased Th2 levels in a biological sample obtained from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with deficient Th1 activity and increased Th2 activity by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with deficient Th1 activity and increased pro-inflammatory cytokine levels by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity. In embodiments, the present disclosure provides a method of treating a patient with deficient Th1 activity and increased pro-inflammatory cytokine levels by administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity.In some embodiments, "deficient Th1-type cytokines" refers to decreased Th1 levels of Th1-type cytokines. In some embodiments, Th1-type cytokines include IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, and granulocyte-macrophage colony-stimulating factor (GMCS). In some embodiments, "increased Th2 activity" is increased Th2 activity compared to a control. In some embodiments, "increased pro-inflammatory cytokine levels" are compared to a control. In some embodiments, "pro-inflammatory cytokines" are IL-4, IL-5, IL10, IL-13, IL-17, or a combination of two or more thereof. In some embodiments, the control is a healthy patient or a healthy patient population.

[0176] "Th1 activity" refers to the number of Th1 cells and / or activity of the Th1 pathway. The Th1 pathway refers to Th1-type cytokines that activate the immune system to suppress tumors. Th1-type cytokines include IFNγ, IL-1β, IL-2, IL-12, TNF-α, TNF-γ, GMCS, or a combination of two or more thereof. Thus, "having deficient Th1 activity" includes a decreased number of Th1-type cytokines or reduced Th1-type cytokine expression.

[0177] "Th2 activity" refers to the number of Th2 cells and / or activity of the Th2 pathway. The Th2 pathway refers to Th2-type cytokines associated with tumor growth or metastasis. Th2-type cytokines include IL-4, IL-5, IL-10, IL-13, IL-17, or a combination of two or more thereof.

[0178] T cell exhaustion is a state of T cells in which T cells lose their effector function and proliferative capacity. Provided herein is a method of reversing T cell exhaustion in a patient in need thereof, comprising administering to the patient an effective amount of an ITK inhibitor. In embodiments, reversing T cell exhaustion comprises treating a patient with T cell exhaustion. In embodiments, reversing T cell exhaustion comprises overcoming T cell exhaustion. In embodiments, a method of reversing T cell exhaustion in a patient in need thereof comprises (i) measuring, in a biological sample obtained from the patient, increased levels of LAG3, increased levels of TIGIT, increased levels of PD-1, or a combination of two or more thereof, relative to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor. In embodiments, a method of reversing T cell exhaustion in a patient in need thereof comprises (i) measuring, in a biological sample obtained from the patient, increased levels of LAG3, relative to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring increased TIGIT levels in a biological sample obtained from the patient, and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring increased PD-1 levels in a biological sample obtained from the patient relative to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring decreased IFNγ levels, decreased granzyme B levels, or a combination thereof, in a biological sample obtained from the patient relative to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring decreased IFNγ levels in a biological sample obtained from the patient relative to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor.In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring decreased granzyme B levels in a biological sample obtained from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a method for reversing T cell exhaustion in a patient in need thereof comprises (i) measuring increased LAG3 levels, increased TIGIT levels, increased PD-1 levels, decreased IFNγ levels, decreased granzyme B levels, or a combination of two or more thereof, in a biological sample obtained from the patient compared to a control, and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a patient is identified as having T cell exhaustion when a biological sample obtained from the patient has (i) increased LAG3 levels, (ii) increased TIGIT levels, (iii) increased PD-1 levels, (iv) decreased IFNγ levels, (v) decreased granzyme B levels, or (vi) a combination of two or more of the foregoing, compared to a control. In some embodiments, the T cells are CD4 T cells. In some embodiments, the patient has cancer. In some embodiments, the method comprising administering an ITK inhibitor increases IFNγ levels, increases granzyme B levels, or a combination thereof, compared to a control, or compared to IFNγ and / or granzyme B levels before administration of the ITK inhibitor. In some embodiments, the method comprising administering an ITK inhibitor decreases LAG3 levels, decreases TIGIT levels, decreases PD-1 levels, or a combination of two or more thereof, compared to a control, or compared to levels of LAG3, TIGIT, PD-1, or a combination of two or more thereof, before administration of the ITK inhibitor. In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of a compound of Formula (A).In embodiments, the ITK inhibitor is a compound of any one of Formulas (1) to (34) or a pharmaceutically acceptable salt thereof.

[0179] The present disclosure provides a method for treating cancer in a subject in need thereof by administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating cancer in a subject in need thereof by administering to the subject an effective amount of a pharmaceutical composition comprising an ITK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of the compound of Formula (A). In some embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof.

[0180] Provided herein are methods of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of an ITK inhibitor, wherein the patient has T cell exhaustion. In some embodiments, the patient has increased LAG3 levels, increased TIGIT levels, increased PD-1 levels, or a combination of two or more thereof, in a biological sample obtained from the patient compared to a control. In some embodiments, the patient has decreased IFNγ levels, decreased granzyme B levels, or a combination of two or more thereof, in a biological sample obtained from the patient compared to a control. In some embodiments, the patient has increased LAG3 levels, increased TIGIT levels, increased PD-1 levels, decreased IFNγ levels, decreased granzyme B levels, or a combination of two or more thereof, in a biological sample obtained from the patient compared to a control. In embodiments, a patient is identified as having T cell exhaustion when a biological sample obtained from the patient has (i) increased LAG3 levels, (ii) increased TIGIT levels, (iii) increased PD-1 levels, (iv) decreased IFNγ levels, (v) decreased granzyme B levels, or (vi) a combination of two or more of the foregoing, compared to a control. In embodiments, the method of treating cancer is increasing IFNγ levels, increasing granzyme B levels, or a combination thereof, compared to a control or compared to IFNγ and / or granzyme B levels before administration of the ITK inhibitor. In embodiments, the method of treating cancer is decreasing LAG3 levels, TIGIT levels, PD-1 levels, or a combination of two or more thereof, compared to a control or compared to levels of LAG3, TIGIT, PD-1, or a combination of two or more thereof, before administration of the ITK inhibitor. In embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of a compound of Formula (A).In embodiments, the ITK inhibitor is a compound of any one of Formulas (1) to (34) or a pharmaceutically acceptable salt thereof.

[0181] Provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) measuring, in a biological sample obtained from the patient, increased levels of LAG3, increased levels of TIGIT, increased levels of PD-1, or a combination of two or more thereof, compared to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor. Provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) measuring, in a biological sample obtained from the patient, decreased levels of IFNγ, decreased levels of Granzyme B, or a combination of two or more thereof, compared to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor. Provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) measuring, in a biological sample obtained from the patient, increased levels of LAG3, increased levels of TIGIT, increased levels of PD-1, decreased levels of IFNγ, decreased levels of Granzyme B, or a combination of two or more thereof, compared to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor. In some embodiments, a patient is identified as having T cell exhaustion when a biological sample obtained from the patient has, relative to a control, (i) increased LAG3 levels, (ii) increased TIGIT levels, (iii) increased PD-1 levels, (iv) decreased IFNγ levels, (v) decreased Granzyme B levels, or (vi) a combination of two or more of the foregoing. In some embodiments, the method of treating cancer involves decreasing LAG3 levels, decreasing TIGIT levels, decreasing PD-1 levels, increasing IFNγ levels, decreasing Granzyme B levels, or a combination of two or more thereof, relative to a control, or relative to the levels of LAG3, TIGIT, PD-1, IFNγ, Granzyme B, or a combination of two or more thereof, prior to administration of an ITK inhibitor. In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of a compound of Formula (A). In some embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof.

[0182] In embodiments, the cancer is a lymphoma. In embodiments, the lymphoma is a T-cell lymphoma. In embodiments, the lymphoma is a peripheral T-cell lymphoma. In embodiments, the lymphoma is a peripheral T-cell lymphoma not otherwise specified. In embodiments, the lymphoma is a cutaneous T-cell lymphoma. In embodiments, the lymphoma is a cutaneous T-cell lymphoma not otherwise specified. In embodiments, the lymphoma is an angioimmunoblastic T-cell lymphoma. In embodiments, the lymphoma is a NK T-cell lymphoma. In embodiments, the cancer is a solid tumor. In embodiments, the cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is prostate cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is leukemia. In embodiments, the cancer is T-cell leukemia. In embodiments, the cancer is T-cell lymphoma, T-cell leukemia, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer.

[0183] In embodiments, the cancer is a relapsed / refractory cancer. In embodiments, the cancer is a relapsed / refractory leukemia. In embodiments, the cancer is a relapsed / refractory T-cell leukemia. In embodiments, the cancer is a relapsed / refractory lymphoma. In embodiments, the lymphoma is a relapsed / refractory T-cell lymphoma. In embodiments, the lymphoma is a relapsed / refractory peripheral T-cell lymphoma. In embodiments, the lymphoma is a relapsed / refractory peripheral T-cell lymphoma not otherwise specified. In embodiments, the lymphoma is a relapsed / refractory cutaneous T-cell lymphoma. In embodiments, the cancer is a relapsed / refractory solid tumor. In embodiments, the relapsed / refractory cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer. In embodiments, the cancer is a relapsed / refractory lung cancer. In embodiments, the cancer is relapsed / refractory colorectal cancer. In embodiments, the cancer is relapsed / refractory pancreatic cancer. In embodiments, the cancer is relapsed / refractory prostate cancer. In embodiments, the cancer is relapsed / refractory breast cancer. In embodiments, the cancer is relapsed / refractory gastric cancer. In embodiments, the cancer is relapsed / refractory head and neck cancer. In embodiments, the relapsed / refractory cancer is T-cell lymphoma, T-cell leukemia, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer.

[0184] The term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It develops primarily in lymphocytes, which are blood cells found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate at which the cancer grows and the type of cell involved. NHL includes aggressive (high-grade) and indolent (low-grade) types. Based on the type of cell involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma (including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified), anaplastic large cell lymphoma, mycosis fungoides, NK T-cell lymphoma, and precursor T-lymphoblastic lymphoma.

[0185] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs, generally characterized by distorted proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and character of the disease—acute or chronic, (2) the type of cell involved—myeloid (myeloid), lymphatic (lymphatic), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood—leukemia or non-leukemia (subleukemia). Exemplary leukemias that may be treated using the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, and leukemia of the genotype. leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0186] The present disclosure provides a method for treating an autoimmune disease in a subject in need thereof by administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating an autoimmune disease in a subject in need thereof by administering to the subject an effective amount of a pharmaceutical composition comprising an ITK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of the compound of Formula (A). In some embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof. In embodiments, the autoimmune disease is an autoimmune lymphoproliferative disease (autoimmune lymphoproliferative syndrome), colitis, or systemic lupus erythematosus. In embodiments, the autoimmune disease is an autoimmune lymphoproliferative disease, ulcerative colitis, or systemic lupus erythematosus. In embodiments, the autoimmune disease is an autoimmune lymphoproliferative disease. In embodiments, the autoimmune disease is colitis. In embodiments, the autoimmune disease is ulcerative colitis. In embodiments, the autoimmune disease is inflammatory bowel disease. In embodiments, the autoimmune disease is systemic lupus erythematosus.

[0187] In embodiments, the autoimmune disease is acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, skin rash, amyloidosis, ankylosinic spondylomyelitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome. autoimmune syndrome, APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinitis, autoimmune thrombocytopenic purpura. purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barot's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal granulomatosis with polyangiitis (CRA) ostomyelitis, CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, conjunctivitis, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitispolyangiitis (GPA) (formerly called Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schoenfeld disease, hemolytic anemia, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus, type 1 diabetes, juvenile myositis, Kawasaki syndrome, Lambert-Eaton vasculitis, lichen planus, lichen sclerosus, lymphocytic conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease, chronic Ménière's disease, microscopic polyangiitis, mixed connective tissue disease Mullen's ulcer, Mucha-Habermann disease, multiple sclerosis, severe myositis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia, ocular cicatricial pemphigoid, ocular neuritis, relapsing rheumatoid arthritis, PANDAS (Streptococcus-associated pediatric autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, Persplanitis (peripheral uveitis), Pemphigus, peripheral neuritis, pericarditis encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, type II, type III autoimmune polyglandular syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary angina pectoris, psoriatic arthritis, genotype Sclerosing cholangitis, psoriatic arthritis, idiopathic pulmonary fibrosis, ganglionic pyoderma, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoid arthritis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-neck syndrome, subacute bacterial endocarditisThese include: endocarditis (SBE), Sazac syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis-giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, bullous dermatoses, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0188] The present disclosure provides a method of treating allergies in a subject in need thereof by administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating allergies in a subject in need thereof by administering to the subject an effective amount of a pharmaceutical composition comprising an ITK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is the free base form of the compound of Formula (A). In embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof. In embodiments, the allergy is an IgE-mediated allergy. In embodiments, the allergy is Th2 cell. In embodiments, the allergy is Th2 cell-mediated inflammation. In embodiments, the allergy is asthma, rhinitis, dermatitis, or psoriasis. In embodiments, the allergy is allergic asthma, allergic rhinitis, atopic dermatitis, allergic dermatitis, or psoriasis. In embodiments, the allergy is asthma, rhinitis, or dermatitis. In embodiments, the allergy is allergic asthma, allergic rhinitis, atopic dermatitis, or allergic dermatitis. In embodiments, the allergy is allergic asthma, allergic rhinitis, atopic dermatitis, or allergic dermatitis. In embodiments, the allergy is allergic asthma. In embodiments, the allergy is asthma. In embodiments, the allergy is allergic rhinitis. In embodiments, the allergy is rhinitis. In embodiments, the allergy is atopic dermatitis. In embodiments, the allergy is allergic dermatitis. In embodiments, the allergy is dermatitis. In embodiments, the allergy is psoriasis.

[0189] The present disclosure provides a method for treating a Th2 / ITK-mediated disease in a subject in need thereof by administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating a Th2 / ITK-mediated disease in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt ... a reduced Th1 + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 +and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating a Th2 / ITK-mediated disease in a subject in need thereof by measuring increased levels of Th2+ cells, increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, or a combination of two or more thereof, in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In embodiments, the method of treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased levels of Th2+ cells in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In embodiments, a method of treating a Th2 / ITK-mediated disease in a subject in need thereof is provided by measuring increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, or a combination of two or more thereof, in a biological sample obtained from the subject, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof.In some embodiments, a method for treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased IL-4 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased IL-5 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased IL-10 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased IL-13 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a Th2 / ITK-mediated disease in a subject in need thereof comprises measuring increased IL-17 levels in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating a Th2 / ITK-mediated disease in a subject in need thereof by measuring increased Th2+ cell levels in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating a Th2 / ITK-mediated disease in a subject in need thereof by measuring increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, or a combination of two or more thereof, in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof.The present disclosure provides a method of treating a Th2 / ITK-mediated disease in a subject in need thereof by administering to the subject an effective amount of a pharmaceutical composition comprising an ITK inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In embodiments, the ITK inhibitor is the free base form of the compound of Formula (A). In embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof. In embodiments, the Th2 / ITK-mediated disease is an autoimmune disease or allergy. In embodiments, the Th2 / ITK-mediated disease is an autoimmune disease. In embodiments, the Th2 / ITK-mediated disease is an allergy. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, a fibrotic disease, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, an eosinophilic disease, a mast cell disease, or a human immunodeficiency virus disease.

[0190] In embodiments of the methods described herein, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, eosinophilic disease, mast cell disease, or human immunodeficiency virus disease. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, esophagitis, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasia, or human immunodeficiency virus disease. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, or pulmonary fibrosis. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, or idiopathic pulmonary fibrosis. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, or conjunctivitis. In embodiments, the Th2 / ITK-mediated disease is scleroderma, pulmonary fibrosis, cirrhosis, or retroperitoneal fibrosis. In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, or conjunctivitis. In embodiments, the Th2 / ITK-mediated disease is scleroderma, idiopathic pulmonary fibrosis, cirrhosis, or retroperitoneal fibrosis. In embodiments, the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, eosinophilic disease, mast cell disease, or human immunodeficiency virus disease. In some embodiments, the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, esophagitis, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasia, or human immunodeficiency virus-mediated disease. In some embodiments, the Th2 / ITK-mediated disease is psoriatic arthritis or vasculitis.

[0191] In embodiments, the Th2 / ITK-mediated disease is atopic dermatitis. In embodiments, the Th2 / ITK-mediated disease is asthma. In embodiments, the Th2 / ITK-mediated disease is rhinitis. In embodiments, the Th2 / ITK-mediated disease is conjunctivitis. In embodiments, the Th2 / ITK-mediated disease is psoriasis. In embodiments, the Th2 / ITK-mediated disease is a fibrotic disease. In embodiments, the fibrotic disease is scleroderma, pulmonary fibrosis, cirrhosis, or retroperitoneal fibrosis. In embodiments, the fibrotic disease is scleroderma, idiopathic pulmonary fibrosis, cirrhosis, or retroperitoneal fibrosis. In embodiments, the Th2 / ITK-mediated disease is scleroderma. In embodiments, the Th2 / ITK-mediated disease is pulmonary fibrosis. In embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In embodiments, the Th2 / ITK-mediated disease is scleroderma. In embodiments, the Th2 / ITK-mediated disease is idiopathic pulmonary fibrosis. In embodiments, the Th2 / ITK-mediated disease is cirrhosis. In embodiments, the Th2 / ITK-mediated disease is retroperitoneal fibrosis. In embodiments, the Th2 / ITK-mediated disease is psoriatic arthritis. In embodiments, the Th2 / ITK-mediated disease is vasculitis. In embodiments, the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome. In embodiments, the Th2 / ITK-mediated disease is chronic obstructive pulmonary disease. In embodiments, the Th2 / ITK-mediated disease is an eosinophilic disease. In embodiments, the eosinophilic disease is esophagitis. In embodiments, the Th2 / ITK-mediated disease is esophagitis. In embodiments, the Th2 / ITK-mediated disease is a mast cell disease. In embodiments, the mast cell disorder is mastocytosis, mast cell activation syndrome, or hereditary alpha tryptasia. In embodiments, the Th2 / ITK-mediated disorder is mastocytosis, mast cell activation syndrome, or hereditary alpha tryptasia. In embodiments, the Th2 / ITK-mediated disorder is mastocytosis. In embodiments, the Th2 / ITK-mediated disorder is mast cell activation syndrome. In embodiments, the Th2 / ITK-mediated disorder is hereditary alpha tryptasia.In embodiments, the Th2 / ITK mediated disease is a human immunodeficiency virus disease.

[0192] The term "Th2 / ITK mediated disease" refers to a disease in which there is increased expression of ITK and / or an increased Th2 cell response, resulting in the secretion or increased secretion of pro-inflammatory cytokines.

[0193] The present disclosure provides a method for detecting decreased Th1 + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 +and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased levels of Th2+ cells, increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, or a combination of two or more thereof in a biological sample obtained from the subject compared to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased levels of IL-4, increased IL-5, increased IL-10, increased IL-13 levels, increased IL-17 levels, or a combination of two or more thereof in a biological sample obtained from the subject compared to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased levels of IL-4 in a biological sample obtained from the subject compared to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased IL-5 levels in a biological sample obtained from the subject compared to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof.The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased IL-10 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased IL-13 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure provides a method of treating an autoimmune disease in a subject in need thereof by measuring increased IL-17 levels in a biological sample obtained from the subject relative to a control and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating an autoimmune disease. In some embodiments, the method is for treating an allergy. In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of a compound of Formula (A). In some embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof.

[0194] The present disclosure provides a method for detecting decreased Th1 expression in a biological sample obtained from a subject compared to a control. + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 +the ratio of T cells, decreased IFNγ levels, decreased CD8+ cytotoxic lymphocyte levels, increased Th2+ cell levels, increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, increased Th17+ T cell levels, increased eosinophil levels, decreased IL-1β levels, decreased IL-2 levels, decreased IL-12 levels, decreased TNF-α levels, decreased TNF-γ levels, decreased GMCS levels, or the like and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof, an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof, to the subject in need thereof. The present disclosure provides a method of treating atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, esophagitis, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasia, or human immunodeficiency virus disease in a subject in need thereof by measuring increased levels of Th2+ cells, increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, or a combination of two or more thereof, in a biological sample obtained from the subject compared to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof.The present disclosure provides a method of treating atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, esophagitis, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasia, or human immunodeficiency virus disease in a subject in need thereof by measuring increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, or a combination of two or more thereof, in a biological sample obtained from the subject relative to a control, and administering to the subject an effective amount of an ITK inhibitor or a pharmaceutically acceptable salt thereof. In embodiments, the method is for treating atopic dermatitis. In embodiments, the method is for treating asthma. In embodiments, the method is for treating rhinitis. In embodiments, the method is for treating conjunctivitis. In embodiments, the method is for treating psoriasis. In embodiments, the method is for treating scleroderma. In embodiments, the method is for treating pulmonary fibrosis. In embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In embodiments, the method is for treating cirrhosis. In embodiments, the method is for treating retroperitoneal fibrosis. In embodiments, the method is for treating psoriatic arthritis. In embodiments, the method is for treating vasculitis. In embodiments, the method is for treating autoimmune lymphoproliferative syndrome. In embodiments, the method is for treating chronic obstructive pulmonary disease. In embodiments, the method is for treating esophagitis. In embodiments, the method is for treating mastocytosis. In embodiments, the method is for treating mast cell activation syndrome. In embodiments, the method is for treating hereditary alpha tryptasia. In embodiments, the method is for treating human immunodeficiency virus-induced disease.In some embodiments, the ITK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the ITK inhibitor is the free base form of the compound of Formula (A). In some embodiments, the ITK inhibitor is a compound of any one of Formulas (1) through (34) or a pharmaceutically acceptable salt thereof.

[0195] Dosage and Administration Regimen The dosage and frequency (single or multiple doses) of an ITK inhibitor administered to a mammal can vary depending on various factors, such as whether the subject is suffering from another disease and the route of administration, the recipient's size, age, sex, health, weight, body mass index, and diet, the nature and extent of symptoms of the disease being treated (e.g., cancer, autoimmune disease, or allergy), the type of concomitant treatment, and complications or other health-related problems resulting from the disease being treated. Other therapeutic regimens or agents may be used in conjunction with the methods and ITK inhibitors described herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the capabilities of one of ordinary skill in the art.

[0196] For any of the compositions and ITK inhibitors described herein, the effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of the ITK inhibitor that is capable of achieving the effects described herein, as measured using methods described herein or known in the art. As is known in the art, the effective amount of an ITK inhibitor for use in humans can also be determined from animal models. For example, a human dose can be formulated to achieve a concentration found to be effective in animals. The human dosage can be adjusted by monitoring efficacy and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on these and other methods is well within the capabilities of one of ordinary skill in the art.

[0197] An "effective amount" is the amount of an ITK inhibitor sufficient to achieve the stated purpose (e.g., achieve the effect for which it is administered, such as increasing Th1 cell activity, treating cancer, treating an autoimmune disease, treating an allergy, increasing Th1 signaling pathway activity, or reducing one or more symptoms of cancer, an autoimmune disease, or an allergy) compared to the absence of the compound. An example of an "effective amount" of an ITK inhibitor is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease (e.g., increasing Th1 cell activity, treating cancer, treating an autoimmune disease, treating an allergy), which may also be referred to as a "therapeutically effective amount." A "reduction" of a symptom(s) refers to a decrease in the severity or frequency of the symptom, or the elimination of the symptom. A "prophylactically effective amount" of an ITK inhibitor is an amount of the ITK inhibitor that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of a disease, condition, or symptom thereof (e.g., increasing Th1 cell activity, treating cancer, treating autoimmune disease, treating allergy), or reducing the likelihood of the onset (or recurrence) of a disease, condition, or symptom thereof (e.g., increasing Th1 cell activity, treating cancer, treating autoimmune disease, treating allergy). A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The exact amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0198] The dosage of the ITK inhibitor may vary depending on the patient's needs. The dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the capabilities of one skilled in the art. Generally, treatment is initiated with a lower dosage that is less than the optimal dose of the ITK inhibitor. Thereafter, the dosage is increased by small increments until the optimal effect is reached under the circumstances. The dosage and interval can be individually adjusted to provide an effective level of the ITK inhibitor for the particular clinical indication being treated. This will provide a treatment regimen appropriate to the severity of the individual's condition.

[0199] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergy, treating Th2 / ITK-mediated disease, reversing T cell exhaustion), the effective amount of the ITK inhibitor is about 0.5 mmol to about 2.0 mmol per day. In some embodiments, the effective amount is about 0.55 mmol to about 2.0 mmol per day. In some embodiments, the effective amount is about 0.5 mmol to about 1.9 mmol per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.8 mmol per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.7 mmol per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.6 mmol per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.55 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.5 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.45 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.4 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.35 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.3 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.25 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 mmol to about 1.2 mmol of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 millimoles to about 1.15 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 millimoles to about 1.1 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.6 millimoles to about 1.05 millimoles of the ITK inhibitor per day.

[0200] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 0.6 millimoles to about 1.0 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.61 millimoles to about 0.99 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.62 millimoles to about 0.98 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.63 millimoles to about 0.97 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.64 millimoles to about 0.96 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.65 millimoles to about 0.95 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.66 millimoles to about 0.94 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.67 millimoles to about 0.93 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.68 millimoles to about 0.92 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.69 millimoles to about 0.91 millimoles of the ITK inhibitor per day.

[0201] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 0.7 millimoles to about 0.9 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.71 millimoles to about 0.89 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.72 millimoles to about 0.88 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.73 millimoles to about 0.87 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.74 millimoles to about 0.86 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.75 millimoles to about 0.85 millimoles of an ITK inhibitor per day. In some embodiments, the effective amount is about 0.76 millimoles to about 0.84 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.77 millimoles to about 0.83 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.78 millimoles to about 0.82 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.79 millimoles to about 0.81 millimoles of the ITK inhibitor per day. In some embodiments, the effective amount is about 0.8 millimoles of the ITK inhibitor per day.

[0202] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 0.25 mmol to about 1.0 mmol of an ITK inhibitor twice per day (BID). In some embodiments, the effective amount is about 0.275 mmol to about 1.0 mmol of an ITK inhibitor twice per day. In some embodiments, the effective amount is about 0.25 mmol to about 0.95 mmol of an ITK inhibitor twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.9 mmol of an ITK inhibitor twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.85 mmol of an ITK inhibitor twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.8 mmol of an ITK inhibitor twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.775 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.75 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.725 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.7 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.675 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.65 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 mmol to about 0.625 mmol of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 millimoles to about 0.6 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 millimoles to about 0.575 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 millimoles to about 0.55 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.3 millimoles to about 0.525 millimoles of the ITK inhibitor administered twice per day.

[0203] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 0.3 millimoles to about 0.5 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.305 millimoles to about 0.495 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.31 millimoles to about 0.49 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.315 millimoles to about 0.485 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.32 millimoles to about 0.48 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.325 millimoles to about 0.475 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.33 millimoles to about 0.47 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.335 millimoles to about 0.465 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.34 millimoles to about 0.46 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.345 millimoles to about 0.455 millimoles of the ITK inhibitor administered twice per day.

[0204] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 0.35 millimoles to about 0.45 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.355 millimoles to about 0.445 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.36 millimoles to about 0.44 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.365 millimoles to about 0.435 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.37 millimoles to about 0.43 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.375 millimoles to about 0.425 millimoles of an ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.38 millimoles to about 0.42 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.385 millimoles to about 0.415 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.39 millimoles to about 0.41 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.395 millimoles to about 0.405 millimoles of the ITK inhibitor administered twice per day. In some embodiments, the effective amount is about 0.4 millimoles of the ITK inhibitor administered twice per day.

[0205] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 250 mg to about 1,000 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 950 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 900 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 850 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 800 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 750 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 700 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 650 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 600 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 250 mg to about 550 mg of the ITK inhibitor per day.

[0206] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 300 mg to about 1,000 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 950 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 900 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 850 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 800 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 750 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 700 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 650 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 600 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 300 mg to about 550 mg of the ITK inhibitor per day.

[0207] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 300 mg to about 500 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 305 mg to about 495 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 310 mg to about 490 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 315 mg to about 485 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 320 mg to about 480 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 325 mg to about 475 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 330 mg to about 470 mg of an ITK inhibitor per day. In some embodiments, the effective amount is about 335 mg to about 465 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 340 mg to about 460 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 345 mg to about 455 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 350 mg to about 450 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 355 mg to about 445 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 360 mg to about 440 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 365 mg to about 435 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 370 mg to about 430 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 375 mg to about 425 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 380 mg to about 420 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 385 mg to about 415 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 390 mg to about 410 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 395 mg to about 405 mg of the ITK inhibitor per day. In some embodiments, the effective amount is about 400 mg of the ITK inhibitor per day.

[0208] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 125 mg to about 500 mg of an ITK inhibitor twice daily (BID). In some embodiments, the effective amount is about 125 mg to about 475 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 450 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 425 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 400 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 375 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 350 mg of an ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 325 mg of the ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 300 mg of the ITK inhibitor twice daily. In some embodiments, the effective amount is about 125 mg to about 275 mg of the ITK inhibitor twice daily.

[0209] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 150 mg to about 500 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 475 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 450 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 425 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 400 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 375 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 350 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 150 mg to about 325 mg of the ITK inhibitor twice daily. In some embodiments, the effective amount is about 150 mg to about 300 mg of the ITK inhibitor twice daily. In some embodiments, the effective amount is about 150 mg to about 275 mg of the ITK inhibitor twice daily.

[0210] In some embodiments of the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion), the effective amount is about 150 mg to about 250 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 152.5 mg to about 247.5 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 155 mg to about 245 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 157.5 mg to about 242.5 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 160 mg to about 240 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 162.5 mg to about 237.5 mg of an ITK inhibitor administered twice daily. In some embodiments, the effective amount is about 165 mg to about 235 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 167.5 mg to about 232.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 170 mg to about 230 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 172.5 mg to about 227.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 175 mg to about 225 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 177.5 mg to about 222.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 180 mg to about 220 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 182.5 mg to about 217.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 185 mg to about 215 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 187.5 mg to about 212.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 190 mg to about 210 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 192.5 mg to about 207.5 mg of the ITK inhibitor taken twice per day. In some embodiments, the effective amount is about 195 mg to about 205 mg of the ITK inhibitor taken twice per day.In some embodiments, the effective amount is about 197.5 mg to about 202.5 mg of the ITK inhibitor twice daily. In some embodiments, the effective amount is about 200 mg of the ITK inhibitor twice daily.

[0211] In some embodiments, the methods described herein (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) include a drug holiday. A "drug holiday" is a period of time, anywhere from several days to several months, during which a patient discontinues taking a drug for treatment. The drug holiday can have a therapeutic benefit, for example, allowing the drug to regain its therapeutic benefit after a period of continuous use. In some embodiments, the present disclosure provides methods that include (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 8 weeks (i.e., a drug holiday); and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the present disclosure provides a method comprising (in this order): (1) administering an ITK inhibitor for about 4 to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 8 weeks (i.e., a drug holiday); and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the present disclosure provides a method comprising (in this order): (1) administering an ITK inhibitor for about 3 to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 8 weeks (i.e., a drug holiday); and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering an ITK inhibitor for about 4 to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 8 weeks (i.e., a drug holiday); and (3) administering the ITK inhibitor for at least 4 weeks.

[0212] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergy, treating Th2 / ITK-mediated disease, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 4 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 6 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 4 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 5 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 4 to about 12 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 3 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 4 to about 12 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 2 weeks, and (3) administering the ITK inhibitor for at least 4 weeks.

[0213] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks.

[0214] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 6 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 6 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 4 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 6 weeks; and (3) administering the ITK inhibitor for at least 4 weeks.

[0215] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks.

[0216] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks, and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks, and (3) administering the ITK inhibitor for at least 2 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks.

[0217] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergy, treating Th2 / ITK-mediated disease, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 6 weeks; and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 6 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 weeks to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks, and (3) administering the ITK inhibitor for at least 2 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 2 to about 6 weeks; and (3) administering the ITK inhibitor for at least 2 weeks.

[0218] In some embodiments, the method (e.g., increasing Th1 activity, treating cancer, treating autoimmune disease, treating allergies, treating Th2 / ITK-mediated diseases, reversing T cell exhaustion) comprises (in this order): (1) administering an ITK inhibitor for about 2 weeks to about 12 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 11 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method comprises (in this order): (1) administering the ITK inhibitor for about 2 weeks to about 10 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 week to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 9 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 8 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 7 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 6 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks, and (3) administering the ITK inhibitor for at least 4 weeks. In some embodiments, the method includes (in this order): (1) administering the ITK inhibitor for about 2 to about 5 weeks, (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks, and (3) administering the ITK inhibitor for at least 2 weeks.In several embodiments, the method includes (in this order): (1) administering an ITK inhibitor for about 2 to about 4 weeks; (2) discontinuing administration of the ITK inhibitor for about 1 to about 4 weeks; and (3) administering the ITK inhibitor for at least 2 weeks.

[0219] Pharmaceutical Compositions Provided herein is a pharmaceutical composition comprising an ITK inhibitor and a pharmaceutically acceptable excipient. The composition is suitable for formulation and administration in vitro or in vivo. Suitable carriers and excipients and their formulation are described in Remington: The Science and Practice of Pharmacy, 21st Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005).

[0220] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solution, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not deleteriously react with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful.

[0221] Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations can contain preservatives to prevent the growth of microorganisms.

[0222] Pharmaceutical compositions can be delivered via intranasal or inhalable solutions or sprays, aerosols, or inhalants. Nasal solutions can be aqueous solutions designed to be administered to the nasal passages via drops or sprays. Nasal solutions can be prepared to resemble nasal mucus in many respects. Thus, nasal solutions are usually isotonic and slightly buffered to maintain a pH of 5-7. In addition, if necessary, antibacterial preservatives similar to those used in eye drops and appropriate drug stabilizers can be included in the formulation. Various commercially available nasal sprays are known, and nasal sprays can contain, for example, antibiotics and antihistamines.

[0223] Oral formulations may contain excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, or powders. In embodiments, oral pharmaceutical compositions will contain an inert diluent or edible carrier, or may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the compositions and preparations may, of course, be varied and may conveniently be about 1 to about 80% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained.

[0224] For parenteral administration in aqueous solution, for example, the solution should be suitably buffered, and the liquid diluent should first be made isotonic with sufficient saline or glucose. Aqueous solutions, particularly sterile aqueous media, are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. For example, a single dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion or injected at the proposed infusion site.

[0225] Sterile injection solution can be prepared by incorporating the required amount of active compound in suitable solvent, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium.For preparing sterile powder for reconstitution of sterile injection solution, vacuum drying and freeze-drying technology can be used to produce powder of active ingredient and any additional desired ingredients.The preparation of higher or higher concentration solutions for direct injection is also intended.Dimethyl sulfoxide can be used as a solvent for very rapid penetration, and delivers high concentration active agent to a small area.

[0226] The preparation of compound can be provided in a sealed container of unit dose or multiple doses, such as ampoules and vials.Therefore, the composition can be in unit dosage form.In this form, the preparation is subdivided into unit dosages that contain appropriate amounts of active ingredients.Therefore, the composition can be administered in various unit dosage forms according to the method of administration.For example, the unit dosage forms suitable for oral administration include but are not limited to powder, tablets, pills, capsules and lozenges.

[0227] In embodiments, the present disclosure provides an orally administrable pharmaceutical composition comprising an ITK inhibitor and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition is an oral composition. In embodiments, the oral composition is a solid oral composition. In embodiments, the oral composition is a liquid oral composition. In embodiments, the pharmaceutical composition is a tablet or capsule. In embodiments, the pharmaceutical composition is a tablet. In embodiments, the pharmaceutical composition is a capsule. In embodiments, the pharmaceutical composition is a powder.

[0228] Embodiments A1 to A69 Embodiment A1. A method of treating a patient having deficient Th1 activity, comprising administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity.

[0229] Embodiment A2. A method of treating a patient having deficient Th1 activity, comprising: (i) detecting in a biological sample obtained from the patient, compared to a control, increased Th2 activity, increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, decreased IFNγ levels, decreased Th1 + T cell count, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 + and (ii) measuring a ratio of T cells, a decreased number of CD8+ cytotoxic lymphocytes, an increased number of Th2+ cells, an increased number of Th17+ T cells, an increased number of eosinophils, or any combination of two or more thereof; and (ii) administering to the patient an effective amount of an ITK inhibitor to increase Th1 activity.

[0230] Embodiment A3. The method of embodiment A1 or A2, wherein the patient has increased Th2 activity compared to a control.

[0231] Embodiment A4. The method of any one of embodiments A1-A3, wherein the patient has increased pro-inflammatory cytokine levels compared to a control.

[0232] Embodiment A5. The method of embodiment A4, wherein the pro-inflammatory cytokine is IL-4, IL-5, IL-10, IL-13, IL-17, or a combination of two or more thereof.

[0233] Embodiment A6. The effective amount for increasing Th1 activity comprises: (a) a Th1 +Increases the number of T cells, (b) Th2 + Th1 vs. T cells + (c) IL-4, which increases the ratio of T cells + CD4 + IFNγ on T cells + CD4 + (d) increasing the ratio of T cells to IL-4; (e) increasing IFNγ production; (f) increasing CD8+ cytotoxic lymphocytes; (g) inhibiting IL-4 production; (h) decreasing Th17+ T cells; (i) a combination of two or more of (a)-(h).

[0234] Embodiment A7. The effective amount for increasing Th1 activity comprises: (a) a Th1 + Increases the number of T cells, (b) Th2 + Th1 vs. T cells + (c) IL-4, which increases the ratio of T cells + CD4 + IFNγ on T cells + CD4 + (d) increase the ratio of T cells; (d) increase IFNγ production; (e) increase CD8+ cytotoxic lymphocytes; (f) inhibit IL-4 production; (g) inhibit IL-13 production; (h) decrease Th2+ cells; (i) decrease Th17+ T cells; (j) decrease eosinophils; or (k) a combination of two or more of (a)-(j).

[0235] Embodiment A8. The method of any one of Embodiments A1-A7, wherein the effective amount for increasing Th1 activity is an amount that inhibits production of cytokines secreted by Th2+ cells.

[0236] Embodiment A9. The method of any one of Embodiments A1-A8 wherein the effective amount for increasing Th1 activity is from about 0.6 millimoles to about 1.6 millimoles of the ITK inhibitor per day.

[0237] Embodiment A10. The method of Embodiment A9 wherein the effective amount for increasing Th1 activity is from about 0.6 millimoles to about 1.0 millimoles of the ITK inhibitor per day.

[0238] Embodiment A11 The method of Embodiment A10 wherein the effective amount for increasing Th1 activity is from about 0.7 millimoles to about 0.9 millimoles of the ITK inhibitor per day.

[0239] Embodiment A12 The method of embodiment A11 wherein the effective amount for increasing Th1 activity is about 0.8 millimoles of the ITK inhibitor per day.

[0240] Embodiment A13 The method of any one of Embodiments A1-A8 wherein the effective amount for increasing Th1 activity is about 0.3 millimoles to about 0.8 millimoles of an ITK inhibitor twice per day.

[0241] Embodiment A14 The method of Embodiment A13 wherein the effective amount for increasing Th1 activity is about 0.3 millimoles to about 0.5 millimoles of an ITK inhibitor twice per day.

[0242] Embodiment A15 The method of Embodiment A14 wherein the effective amount for increasing Th1 activity is about 0.35 millimoles to about 0.45 millimoles of an ITK inhibitor twice per day.

[0243] Embodiment A16 The method of embodiment A15 wherein the effective amount for increasing Th1 activity is about 0.4 millimoles of an ITK inhibitor twice per day.

[0244] Embodiment A17. A method of treating cancer, an autoimmune disease, or an allergy in a patient in need thereof, comprising administering to the patient from about 0.6 millimoles per day to about 1.6 millimoles per day of an ITK inhibitor.

[0245] Embodiment A18. A method of treating cancer, autoimmune disease, or allergy in a patient in need thereof, comprising: (i) detecting decreased Th1 in a biological sample obtained from the subject compared to a control. + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 + and (ii) measuring a ratio of T cells, decreased IFNγ levels, decreased CD8+ cytotoxic lymphocyte levels, increased Th2+ cell levels, increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, increased Th17+ T cell levels, increased eosinophil levels, decreased IL-1β levels, decreased IL-2 levels, decreased IL-12 levels, decreased TNF-α levels, decreased TNF-γ levels, decreased GMCS levels, or a combination of two or more thereof; and (ii) administering to the patient between about 0.6 millimoles per day and about 1.6 millimoles per day of an ITK inhibitor.

[0246] Embodiment A19. The method of embodiment A17 or A18, wherein the cancer is T-cell lymphoma or T-cell leukemia.

[0247] Embodiment A20. The method of embodiment A17 or A18, wherein the cancer is peripheral T-cell lymphoma.

[0248] Embodiment A21. The method of embodiment A17 or A18, wherein the cancer is peripheral T-cell lymphoma not otherwise specified.

[0249] Embodiment A22. The method of embodiment A17 or A18, wherein the cancer is cutaneous T-cell lymphoma.

[0250] Embodiment A23 The method of embodiment A17 or A18, wherein the cancer is a solid tumor.

[0251] Embodiment A24. The method of embodiment A17 or A18, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer.

[0252] Embodiment A25. The method of embodiment A17 or A18, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, renal cancer, or head and neck cancer.

[0253] Embodiment A26. The method of any one of embodiments A17-A25, wherein the cancer is a relapsed / refractory cancer.

[0254] Embodiment A27. The method of embodiment A17 or A18, wherein the autoimmune disease is an autoimmune lymphoproliferative disorder, ulcerative colitis, or systemic lupus erythematosus.

[0255] Embodiment A28. The method of embodiment A17 or A18, wherein the autoimmune disease is an autoimmune lymphoproliferative disorder, colitis, inflammatory bowel disease, or systemic lupus erythematosus.

[0256] Embodiment A29. The method of embodiment A17 or A18, wherein the allergy is asthma, dermatitis, rhinitis, or psoriasis.

[0257] Embodiment A30. A method of treating a Th2 / ITK mediated disease in a patient in need thereof, comprising administering to the patient from about 0.6 mmol per day to about 1.6 mmol per day of an ITK inhibitor.

[0258] Embodiment A31. A method of treating a Th2 / ITK mediated disease in a patient in need thereof, comprising: (i) detecting decreased Th1 in a biological sample obtained from the subject compared to a control. + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 +and (ii) measuring a ratio of T cells, decreased IFNγ levels, decreased CD8+ cytotoxic lymphocyte levels, increased Th2+ cell levels, increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, increased Th17+ T cell levels, increased eosinophil levels, decreased IL-1β levels, decreased IL-2 levels, decreased IL-12 levels, decreased TNF-α levels, decreased TNF-γ levels, decreased GMCS levels, or a combination of two or more thereof; and (ii) administering to the patient between about 0.6 millimoles per day and about 1.6 millimoles per day of an ITK inhibitor.

[0259] Embodiment A32. The method of embodiment A30 or A31, wherein the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, eosinophilic disease, mast cell disease, or human immunodeficiency virus disease.

[0260] Embodiment A33 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is atopic dermatitis.

[0261] Embodiment A34 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disorder is asthma.

[0262] Embodiment A35 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is rhinitis.

[0263] Embodiment A36 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is conjunctivitis.

[0264] Embodiment A37 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is psoriasis.

[0265] Embodiment A38 The method of embodiment A30 or A31 wherein the Th2 / ITK-mediated disorder is a fibrotic disorder.

[0266] Embodiment A39. The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is scleroderma.

[0267] Embodiment A40 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is pulmonary fibrosis.

[0268] Embodiment A41. The method of embodiment A40, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0269] Embodiment A42 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is cirrhosis.

[0270] The method of embodiment A30 or A31, wherein the Th2 / ITK-mediated disorder is retroperitoneal fibrosis. Th2 / ITK-mediated disorder.

[0271] Embodiment A44 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is psoriatic arthritis.

[0272] Embodiment A45 The method of embodiment A30 or A31 wherein the Th2 / ITK-mediated disease is vasculitis.

[0273] Embodiment A46 The method of embodiment A30 or A31 wherein the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome.

[0274] Embodiment A47 The method of embodiment A30 or A31 wherein the Th2 / ITK-mediated disease is chronic obstructive pulmonary disease.

[0275] Embodiment A48 The method of embodiment A30 or A31 wherein the Th2 / ITK-mediated disorder is an eosinophilic disorder.

[0276] Embodiment A49. The method of embodiment A48, wherein the eosinophilic disease is esophagitis.

[0277] Embodiment A50 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disorder is a mast cell disorder.

[0278] Embodiment A51 The method of embodiment A50, wherein the mast cell disorder is mastocytosis, mast cell activation syndrome, or hereditary alpha tryptasia.

[0279] Embodiment A52 The method of embodiment A30 or A31 wherein the Th2 / ITK mediated disease is a human immunodeficiency virus disease.

[0280] Embodiment A53 The method of any one of Embodiments A1-A52, wherein the ITK inhibitor has selectivity for ITK that is at least 50-fold greater than its selectivity for resting lymphocyte kinase.

[0281] Embodiment A54 The method of any one of Embodiments A1-A52, wherein the ITK inhibitor has selectivity for ITK that is at least 100-fold greater than its selectivity for resting lymphocyte kinase.

[0282] Embodiment A55. The method of any one of Embodiments A1-A54, wherein the ITK inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0283] [ka]

[0284] Embodiment A56. The method of any one of Embodiments A17-A55 comprising administering to the patient about 0.6 millimoles to about 1.2 millimoles per day of an ITK inhibitor.

[0285] Embodiment A57. The method of Embodiment A56 comprising administering to the patient about 0.6 millimoles to about 1.0 millimoles per day of the ITK inhibitor.

[0286] Embodiment A58. The method of Embodiment A56 comprising administering to the patient about 0.7 millimoles to about 0.9 millimoles per day of the ITK inhibitor.

[0287] Embodiment A59. The method of embodiment A56 comprising administering to the patient about 0.8 millimoles per day of an ITK inhibitor.

[0288] Embodiment A60. The method of any one of Embodiments A17-A55 comprising administering to the patient about 0.3 millimoles to about 0.8 millimoles of an ITK inhibitor twice per day.

[0289] Embodiment A61. The method of Embodiment A60 comprising administering to the patient about 0.3 millimoles to about 0.5 millimoles of an ITK inhibitor twice per day.

[0290] Embodiment A62. The method of Embodiment A60 comprising administering to the patient about 0.35 millimoles to about 0.45 millimoles of an ITK inhibitor twice daily.

[0291] Embodiment A63. The method of embodiment A60 comprising administering to the patient about 0.4 millimoles of an ITK inhibitor twice per day.

[0292] Embodiment A64. The method of any one of embodiments A6-A16, A18-A29, and A31-A63, wherein (i) comprises measuring increased levels of Th2+ cells, increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, or a combination of two or more thereof, in a biological sample obtained from the subject compared to a control.

[0293] Embodiment A65. The method of embodiment A64, wherein (i) comprises measuring increased levels of Th2+ cells in a biological sample obtained from the subject, as compared to a control.

[0294] The method of embodiment A64, wherein (i) comprises measuring, in a biological sample obtained from the subject, an increased level of IL-4, an increased level of IL-5, an increased level of IL-10, an increased level of IL-13, an increased level of IL-17, or a combination of two or more thereof, compared to a control.

[0295] Embodiment A67. The method of any one of embodiments A1 to A66, comprising, in this order: (i) administering the ITK inhibitor for about 4 weeks to about 12 weeks; (ii) discontinuing administration of the ITK inhibitor for about 1 week to about 8 weeks; and (iii) administering the ITK inhibitor for at least 4 weeks.

[0296] Embodiment A68. The method of any one of embodiments A1 to A66, comprising, in this order: (i) administering an ITK inhibitor for about 4 weeks to about 12 weeks; (ii) discontinuing administration of the ITK inhibitor for about 1 week to about 8 weeks; and (iii) administering the ITK inhibitor for about 4 weeks to about 12 weeks.

[0297] Embodiment A69. The method of Embodiment A67 or A68 further comprising repeating steps (ii) and (iii).

[0298] Embodiments B1 to B68. Embodiment B1. A method of treating cancer, an autoimmune disease, or an allergy in a patient in need thereof, comprising administering to the patient from about 250 mg to about 1,000 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is:

[0299] [ka] That's the method.

[0300] Embodiment B2. The method of embodiment B1 for treating cancer.

[0301] Embodiment B3. The method of embodiment B2, wherein the cancer is lymphoma.

[0302] Embodiment B4. The method of embodiment B3, wherein the lymphoma is a T-cell lymphoma.

[0303] Embodiment B5. The method of embodiment B3, wherein the lymphoma is peripheral T-cell lymphoma.

[0304] Embodiment B6. The method of embodiment B3, wherein the lymphoma is peripheral T-cell lymphoma not otherwise specified.

[0305] Embodiment B7 The method of embodiment B3, wherein the lymphoma is cutaneous T-cell lymphoma.

[0306] Embodiment B8. The method of embodiment B2, wherein the cancer is a solid tumor.

[0307] Embodiment B9. The method of embodiment B2, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, or head and neck cancer.

[0308] Embodiment B10. The method of embodiment B2, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, gastric cancer, renal cancer, or head and neck cancer.

[0309] Embodiment B11. The method of embodiment B2, wherein the cancer is leukemia.

[0310] Embodiment B12. The method of embodiment B11, wherein the leukemia is T-cell leukemia.

[0311] Embodiment B13. The method of any one of Embodiments B1-B12, wherein the cancer is a relapsed / refractory cancer.

[0312] Embodiment B14. The method of embodiment B1 for treating an autoimmune disease.

[0313] Embodiment B15. The method of embodiment B14, wherein the autoimmune disease is an autoimmune lymphoproliferative disease.

[0314] Embodiment B16. The method of embodiment B14, wherein the autoimmune disease is colitis.

[0315] Embodiment B17. The method of embodiment B16, wherein the colitis is ulcerative colitis.

[0316] Embodiment B18. The method of embodiment B14, wherein the autoimmune disease is inflammatory bowel disease.

[0317] Embodiment B19. The method of embodiment B14, wherein the autoimmune disease is systemic lupus erythematosus.

[0318] Embodiment B20. The method of embodiment B1 for treating allergies.

[0319] Embodiment B21. The method of Embodiment B20 wherein the allergy is asthma, dermatitis, rhinitis, or psoriasis.

[0320] Embodiment B22. The method of Embodiment B20 wherein the allergy is allergic asthma, atopic dermatitis, allergic dermatitis, allergic rhinitis, or psoriasis.

[0321] Embodiment B23. A method for treating a Th2 / ITK mediated disease in a patient in need thereof, comprising administering to the patient from about 250 mg to about 1,000 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is:

[0322] [ka] That's the method.

[0323] Embodiment B24. The method of embodiment B23, wherein the Th2 / ITK-mediated disease is atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, scleroderma, pulmonary fibrosis, cirrhosis, retroperitoneal fibrosis, psoriatic arthritis, vasculitis, autoimmune lymphoproliferative syndrome, chronic obstructive pulmonary disease, eosinophilic disease, mast cell disease, or human immunodeficiency virus disease.

[0324] Embodiment B25 The method of embodiment B23, wherein the Th2 / ITK mediated disease is atopic dermatitis.

[0325] Embodiment B26 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is asthma.

[0326] Embodiment B27 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is rhinitis.

[0327] Embodiment B28 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is conjunctivitis.

[0328] Embodiment B29 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is psoriasis.

[0329] Embodiment B30 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is a fibrotic disease.

[0330] Embodiment B31 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is scleroderma.

[0331] Embodiment B32 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is pulmonary fibrosis.

[0332] Embodiment B33. The method of embodiment B32, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0333] Embodiment B34 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is cirrhosis.

[0334] Embodiment B35 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is retroperitoneal fibrosis.

[0335] Embodiment B36 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is psoriatic arthritis.

[0336] Embodiment B37 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is vasculitis.

[0337] Embodiment B38 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome.

[0338] Embodiment B39 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is chronic obstructive pulmonary disease.

[0339] Embodiment B40 The method of embodiment B23, wherein the Th2 / ITK-mediated disorder is an eosinophilic disorder.

[0340] Embodiment B41. The method of embodiment B40, wherein the eosinophilic disease is esophagitis.

[0341] Embodiment B42 The method of embodiment B23, wherein the Th2 / ITK-mediated disorder is a mast cell disorder.

[0342] Embodiment B43 The method of embodiment B42, wherein the mast cell disorder is mastocytosis, mast cell activation syndrome, or hereditary alpha tryptasia.

[0343] Embodiment B44 The method of embodiment B23, wherein the Th2 / ITK-mediated disease is a human immunodeficiency virus disease.

[0344] Embodiment B45. The method of any one of Embodiments B1 to B44 comprising administering to the patient from about 250 mg to about 900 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0345] Embodiment B46. The method of Embodiment B45 comprising administering to the patient from about 250 mg to about 800 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0346] Embodiment B47. The method of Embodiment B45 comprising administering to the patient from about 250 mg to about 700 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0347] Embodiment B48. The method of Embodiment B45 comprising administering to the patient from about 250 mg to about 600 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0348] Embodiment B49. The method of Embodiment B45 comprising administering to the patient from about 250 mg to about 550 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0349] Embodiment B50. The method of Embodiment B45 comprising administering to the patient from about 300 mg to about 500 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0350] Embodiment B51. The method of Embodiment B45 comprising administering to the patient from about 350 mg to about 450 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0351] Embodiment B52. The method of Embodiment B45 comprising administering to the patient about 400 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0352] Embodiment B53. The method of any one of Embodiments B1 to B44 comprising administering to the patient about 125 mg to about 500 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0353] Embodiment B54. The method of Embodiment B53 comprising administering to the patient about 125 mg to about 450 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0354] Embodiment B55. The method of Embodiment B53 comprising administering to the patient about 125 mg to about 400 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0355] Embodiment B56. The method of Embodiment B53 comprising administering to the patient about 125 mg to about 350 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0356] Embodiment B57. The method of Embodiment B53 comprising administering to the patient about 125 mg to about 300 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0357] Embodiment B58. The method of Embodiment B53 comprising administering to the patient about 125 mg to about 275 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0358] Embodiment B59. The method of Embodiment B53 comprising administering to the patient about 150 mg to about 250 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0359] Embodiment B60. The method of Embodiment B53 comprising administering to the patient about 175 mg to about 225 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0360] Embodiment B61. The method of Embodiment B53 comprising administering to the patient about 200 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof twice daily.

[0361] Embodiment B62. The method of any one of Embodiments B1 to B61, comprising, in this order: (i) administering a compound of Formula (A) or a pharmaceutically acceptable salt thereof for about 4 weeks to about 12 weeks; (ii) discontinuing administration of the compound of Formula (A) or a pharmaceutically acceptable salt thereof for about 1 week to about 8 weeks; and (iii) administering a compound of Formula (A) or a pharmaceutically acceptable salt thereof for at least 4 weeks.

[0362] Embodiment B63. The method of any one of Embodiments B1 to B61, comprising, in this order: (i) administering a compound of Formula (A) or a pharmaceutically acceptable salt thereof for about 4 weeks to about 12 weeks; (ii) discontinuing administration of the compound of Formula (A) or a pharmaceutically acceptable salt thereof for about 1 week to about 8 weeks; and (iii) administering a compound of Formula (A) or a pharmaceutically acceptable salt thereof for about 4 weeks to about 12 weeks.

[0363] Embodiment B64. The method of embodiment B62 or B63 further comprising repeating steps (ii) and (iii).

[0364] Embodiment B65. A biological sample obtained from a subject prior to administration of a compound of Formula (A) or a pharmaceutically acceptable salt thereof to the patient is found to exhibit decreased Th1 + T cell levels, decreased Th2 + Th1 vs. T cells + T cell ratio, decreased IL-4 + CD4 + IFNγ on T cells + CD4 + The method of any one of embodiments B1-B64, further comprising measuring the ratio of T cells, decreased levels of IFNγ, decreased levels of CD8+ cytotoxic lymphocytes, increased levels of Th2+ cells, increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, increased levels of Th17+ T cells, increased levels of eosinophils, decreased levels of IL-1β, decreased levels of IL-2, decreased levels of IL-12, decreased levels of TNF-α, decreased levels of TNF-γ, decreased levels of GMCS, or a combination of two or more thereof.

[0365] Embodiment B66. The method of any one of Embodiments B1 to B64, further comprising measuring increased levels of Th2+ cells, increased levels of IL-4, increased levels of IL-5, increased levels of IL-10, increased levels of IL-13, increased levels of IL-17, or a combination of two or more thereof, in a biological sample obtained from the subject, relative to a control, prior to administering to the patient a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0366] Embodiment B67. The method of any one of Embodiments B1 to B64, further comprising measuring increased IL-4 levels, increased IL-5 levels, increased IL-10 levels, increased IL-13 levels, increased IL-17 levels, or a combination of two or more thereof, in a biological sample obtained from the subject, relative to a control, prior to administering to the patient a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0367] Embodiment B68. The method of any one of Embodiments B1 to B64, further comprising measuring increased Th2+ cell levels in a biological sample obtained from the subject, compared to a control, prior to administering to the patient a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0368] Embodiments C1 to C4 Embodiment C1. A pharmaceutical composition comprising about 150 mg to about 250 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of Formula (A) is:

[0369] [ka] A pharmaceutical composition comprising:

[0370] Embodiment C2. The pharmaceutical composition of embodiment 125, comprising about 200 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof.

[0371] Embodiment C3. A pharmaceutical composition comprising about 300 mg to about 500 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in a single dose or divided doses, and the compound of Formula (A) or a pharmaceutically acceptable salt thereof is:

[0372] [ka] A pharmaceutical composition comprising:

[0373] Embodiment C4. The pharmaceutical composition of embodiment 127, comprising about 400 mg of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in a single dose or in divided doses.

[0374] Embodiments D1 to D53 Embodiment D1. A method of reversing T cell exhaustion in a patient in need thereof, comprising administering to the patient an effective amount of an ITK inhibitor.

[0375] Embodiment D2. A method of reversing T cell exhaustion in a patient in need thereof, comprising: (i) measuring, in a biological sample obtained from the patient, increased levels of LAG3, increased levels of TIGIT, increased levels of PD-1, or a combination of two or more thereof, compared to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor.

[0376] Embodiment D3. A method of reversing T cell exhaustion in a patient in need thereof, comprising: (i) measuring decreased IFN levels, decreased granzyme B levels, or a combination of two or more thereof, in a biological sample obtained from the patient compared to a control; and (ii) administering to the patient an effective amount of an ITK inhibitor.

[0377] Embodiment D4. A method of reversing T cell exhaustion in a patient in need thereof, comprising: (i) measuring, in a biological sample obtained from the patient, increased level...

Claims

1. A pharmaceutical composition for treating allergies, cancer, or autoimmune diseases, comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) is 【Chemistry 1】 A pharmaceutical composition wherein the compound represented by formula (A) is administered to the patient in an amount of approximately 250 mg to approximately 1,000 mg per day.

2. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (A) is administered to the patient in an amount of about 250 mg to about 900 mg per day, or in an amount of about 125 mg to about 500 mg twice per day.

3. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (A) is administered to the patient in an amount of about 400 mg per day, or in an amount of about 200 mg twice per day.

4. A pharmaceutical composition according to any one of claims 1 to 3 for treating an autoimmune disease, wherein the autoimmune disease is an autoimmune lymphoproliferative disorder, colitis, inflammatory bowel disease, or systemic lupus erythematosus.

5. A pharmaceutical composition according to any one of claims 1 to 3 for treating an allergy, wherein the allergy is atopic dermatitis, allergic asthma, allergic dermatitis, allergic rhinitis, or psoriasis.

6. The pharmaceutical composition according to claim 3, wherein the allergy is atopic dermatitis.

7. A pharmaceutical composition according to any one of claims 1 to 3 for treating cancer, wherein the cancer is lymphoma, leukemia, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, stomach cancer, or head and neck cancer.

8. The pharmaceutical composition according to any one of claims 1 to 3, further comprising measuring, in a biological sample obtained from a subject, an increased Th2+ cell level, an increased IL-4 level, an increased IL-5 level, an increased IL-10 level, an increased IL-13 level, an increased IL-17 level, or a combination of two or more of these, compared to a control.

9. The following steps: (i) A step of administering the compound of formula (A) or a pharmaceutically acceptable salt thereof for about 4 weeks to about 12 weeks. (ii) A step of discontinuing the administration of the compound of formula (A) or a pharmaceutically acceptable salt thereof for about one to about eight weeks, and (iii) A step of administering the compound of formula (A) or a pharmaceutically acceptable salt thereof for at least four weeks. A pharmaceutical composition according to any one of claims 1 to 3, comprising the following in order.

10. A pharmaceutical composition comprising a compound represented by formula (A) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the compound represented by formula (A) is 【Chemistry 2】 And, (i) Approximately 200 mg of the compound represented by formula (A) or a pharmaceutically acceptable salt thereof, (ii) Approximately 400 mg of the compound represented by formula (A) or a pharmaceutically acceptable salt thereof, in a single dose or divided dose. A pharmaceutical composition containing

11. A pharmaceutical composition comprising an ITK inhibitor for treating Th2 / ITK-mediated diseases, treating deficient Th1 activity, treating T cell exhaustion, or treating cancer in patients with T cell exhaustion.

12. A pharmaceutical composition according to claim 11 for treating a Th2 / ITK-mediated disease, wherein the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome, atopic dermatitis, asthma, rhinitis, conjunctivitis, psoriasis, fibrosis, psoriatic arthritis, vasculitis, chronic obstructive pulmonary disease, eosinophilic disease, mast cell disease, or human immunodeficiency virus disease.

13. The pharmaceutical composition according to claim 12, wherein the Th2 / ITK-mediated disease is autoimmune lymphoproliferative syndrome or atopic dermatitis.

14. A pharmaceutical composition according to claim 11 for treating T cell exhaustion or cancer in a patient having T cell exhaustion, further comprising measuring, in a biological sample obtained from a patient, an increased LAG3 level, an increased TIGIT level, an increased PD-1 level, a decreased IFNγ level, a decreased granzyme B level, or a combination of two or more of these, compared to a control.

15. A pharmaceutical composition according to claim 11 for treating deficient Th1 activity, further comprising measuring, in a biological sample obtained from a patient, increased Th2 activity, increased IL-4 level, increased IL-5 level, increased IL-10 level, increased IL-13 level, increased IL-17 level, decreased IFNγ level, decreased Th1+ T cell count, decreased Th1+ T cell ratio to decreased Th2+ T cell count, decreased IFNγ+CD4+ T cell ratio to decreased IL-4+CD4+ T cell count, decreased CD8+ cytotoxic lymphocyte count, increased Th2+ cell count, increased Th17+ T cell count, increased eosinophil count, or two or more combinations thereof, compared to a control.

16. The pharmaceutical composition according to any one of claims 11 to 15, further comprising measuring, in a biological sample obtained from a patient, an increased Th2+ cell level, an increased IL-4 level, an increased IL-5 level, an increased IL-10 level, an increased IL-13 level, an increased IL-17 level, or a combination of two or more of these, compared to a control.

17. The pharmaceutical composition according to any one of claims 11 to 15, wherein the ITK inhibitor is administered in an amount of about 0.6 mmol to about 1.6 mmol per day, or twice per day in an amount of about 0.3 mmol to about 0.8 mmol.

18. The pharmaceutical composition according to claim 16, wherein the ITK inhibitor is administered in an amount of about 0.6 mmol to about 1.0 mmol per day, or twice per day in an amount of about 0.3 mmol to about 0.5 mmol.

19. The ITK inhibitor is a compound represented by formula (A): 【Transformation 3】 The pharmaceutical composition according to any one of claims 11 to 15, or a pharmaceutically acceptable salt thereof.

20. The ITK inhibitor is a compound of formula (I) having the following formula or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 During the ceremony, Ring A is 【Transformation 5】 And, R 1 independently consists of hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH 2 X 1, -OCX 1 3, -OCH 2 X 1, -OCHX 1 2, -CN, -SO n1 R 1D, -SO v1 NR 1A R 1B, -NHC(O)NR 1A R 1B, -N(O) m1, -NR 1A R 1B, -C(O)R 1C, -C(O)-OR 1C, -C(O)NR 1A R 1B, -OR 1D, -NR 1A SO 2 R 1D, -NR 1A C(O)R 1C, -NR 1A C(O)OR 1C, -NR 1A OR 1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R2 is independently hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2A R2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C, -NR 2A OR 2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 3 is independently hydrogen, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCX 3 3 , -OCH 2 , -NHC(O)NR 3A R 3B , -N(O) m3 , -NR 3A R 3B , -C(O)R 3C , -C(O)-OR 3C , -C(O)NR 3A R 3B , -OR 3D , -NR 3A SO 2 R 3D , -NR 3A C(O)R 3C , -NR 3A C(O)OR 3C, -NR 3A OR 3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 4 independently consists of hydrogen, halogen, -CX 4 3, -CHX 4 2, -CH 2 X 4, -OCX 4 3, -OCH 2 X 4, -OCHX 4 2, -CN, -SO n 4 R 4D, -SO v 4 NR 4A R 4B, -NHC(O)NR 4A R 4B, -N(O) m 4, -NR 4A R 4B, -C(O)R 4C, -C(O)-OR 4C, -C(O)NR 4A R 4B, -OR 4D, -NR 4A SO 2 R 4D, -NR 4A C(O)R 4C, -NR 4A C(O)OR 4C, -NR 4A OR 4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 5 is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. L1 is an -O-, -S-, or substituted or unsubstituted C1-C2 alkylene, or a substituted or unsubstituted two-membered heteroalkylene. L2 is a bond, -NH-, or -NHC(O)-, L3 is a bond, -S(O)2-, -N(R6)-, -O-, -S-, -C(O)-, -C(O)N(R6)-, -N(R6)C(O)-, -N(R6)C(O)NH-, -NHC(O)N(R6)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R 6 is independently hydrogen, -CX 6 3, -CHX 6 2, -CH 2 X 6, -CN, -C(O)R 6C, -C(O)OR 6C, -C(O)NR 6A R 6B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L4 is a substituted or unsubstituted heterocycloalkylene. E is, 【Transformation 6】 And, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R6A, R6B, and R6C are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R1A and R1B are bonded to the same nitrogen atom. The substituents may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, R2A and R2B substituents bonded to the same nitrogen atom may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, R3A and R3B substituents bonded to the same nitrogen atom may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, R4A and R4B substituents bonded to the same nitrogen atom may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, R6A and R6B substituents bonded to the same nitrogen atom may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, R7A and R7B substituents bonded to the same nitrogen atom may optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds. Each X, X1, X2, X3, X4, and X6 is independently -F, -Cl, -Br, or -I. n1, n2, n3, and n4 are independent integers between 0 and 2. m1, m2, m3, m4, v1, v2, v3, and v4 are independently 1 or 2. R 15 independently consists of hydrogen, halogen, -CX 15 3, -CHX 15 2, -CH 2 X 15, -CN, -SO n 15 R 15D, -SO v 15 NR 15A R 15B, -NHNR 15A R 15B, -ONR 15A R 15B, -NHC=(O)NHNR 15A R 15B, -N(O) m 15, -NR 15A R 15B, -NHC(O)NR 15A R 15B, -C(O)R 15C, -C(O)-OR 15C, -C(O)NR 15A R 15B, -OR 15D, -NR 15A SO 2 R 15D, -NR 15A C(O)R 15C, -NR 15A C(O)OR 15C, -NR 15A OR 15C, -OCX 15 3, -OCHX 15 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 16 independently consists of hydrogen, halogen, -CX 16 3, -CHX 16 2, -CH 2 X 16, -CN, -SO n 16 R 16D, -SO v 16 NR 16A R 16B, -NHNR 16A R 16B, -ONR 16A R 16B, -NHC=(O)NHNR 16A R 16B, -N(O) m 16, -NR 16A R 16B, -NHC(O)NR 16A R 16B, -C(O)R 16C, -C(O)-OR 16C, -C(O)NR 16A R 16B, -OR 16D, -NR 16A SO 2 R 16D, -NR 16A C(O)R 16C, -NR 16A C(O)OR 16C, -NR 16A OR 16C, -OCX 16 3, -OCHX 16 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 17 is independently hydrogen, halogen, -CX 17 3 , -CHX 17 2 , -CH 2 R 17B , -NHC=(O)NHNR 17A R 17B , -N(O) m17 , -NR 17A R 17B , -NHC(O)NR 17A R 17B , -C(O)R 17C , -C(O)-OR 17C , -C(O)NR 17A R 17B, ​​-OR 17D, -NR 17A SO 2 R 17D, -NR 17A C(O)R 17C, -NR 17A C(O)OR 17C, -NR 17A OR 17C, -OCX 17 3, -OCHX 17 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 18 is independently hydrogen, -CX 18 3, -CHX 18 2, -CH 2 X 18, -C(O)R 18C, -C(O)OR 18C, -C(O)NR 18A R 18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R15A, R15B, R15C, R15D, R16A, R16B, R16C, R16D, R17A, R17B, R17C, R17D, R18A, R18B, and R18C are independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R15A and R15B substituents bonded to the same nitrogen atom can optionally link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R16A bonded to the same nitrogen atom The R 16B substituent may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, the R 17A and R 17B substituents bonded to the same nitrogen atom may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and the R 18A and R 18B substituents bonded to the same nitrogen atom may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each of X, X15, X16, X17, and X18 is independently -F, -Cl, -Br, or -I. n15, n16, and n17 are independent integers between 0 and 2. v15, v16, and v17 are independently 1 or 2. m15, m16, and m17 are independently 1 or 2. A pharmaceutical composition according to any one of claims 11 to 15.

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